Cannabinoid receptor ligands

ABSTRACT

There are disclosed compounds of the formula  
                 
 
     a prodrug thereof, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound or of said prodrug; which exhibit anti-inflammatory and immunodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds and methods of using the compounds for the treatment of various diseases and conditions.

BACKGROUND OF THE INVENTION

[0001] This invention relates to cannabinoid receptor ligands and, moreparticularly, to compounds that bind to cannabinoid (CB₂) receptors.Compounds according to the present invention generally exhibitanti-inflammatory and immunomodulatory activity and are useful intreating conditions characterized by inflammation and immunomodulatoryirregularities. Examples of conditions which may be treated include, butare not limited to, rheumatoid arthritis, asthma, allergy, psoriasis,Crohn's disease, systemic lupus erythematosus, multiple sclerosis,diabetes, cancer, glaucoma, osteoporosis, renal ischemia, cerebralstroke, cerebral ischemia, and nephritis. The invention also relates topharmaceutical compositions containing said compounds.

[0002] Cannabinoid receptors belong to the superfamily of G-proteincoupled receptors. They are classified into the predominantly neuronalCB1 receptors and the predominantly peripheral CB2 receptors. While theeffects of CB1 receptors are principally associated with the centralnervous system, CB2 receptors are believed to have peripheral effectsrelated to bronchial constriction, immunomodulation and inflammation. Assuch, a selective CB2 receptor binding agent is expected to havetherapeutic utility in the control of diseases associated withinflammation, immunomodulation and bronchial constriction such asrheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis,diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebralischemia, nephritis, inflammatory disorders of the lungs andgastrointestinal tract, and respiratory tract disorders such asreversible airway obstruction, chronic asthma and bronchitis (see, e.g.,R. G. Pertwee, Curr. Med. Chem. 6(8), (1999), 635).

[0003] Various compounds have reportedly been developed which interactwith CB₂ receptors and/or which have, inter alia, anti-inflammatoryactivity associated with cannabinoid receptors. See, e.g., U.S. Pat.Nos. 5,338,753, 5,462,960, 5,532,237, 5,925,768, 5,948,777, 5,990,170,6,013,648 and 6,017,919.

SUMMARY OF THE INVENTION

[0004] This invention relates to compounds of formula I:

[0005] a prodrug thereof, or a pharmaceutically acceptable salt, solvateor stereoisomer of the compound or of said prodrug; wherein:

[0006] R¹ is H, alkyl, haloC₁-C₆ alkyl, cycloalkyl, cycloalkylNH—,arylalkyl, heterocycloalkyl, heteroaryl, N(R²)₂, or NR²aryl,unsubstituted aryl or aryl substituted with one to three X;

[0007] R² is the same or different in each occurrence and isindependently selected from H or C₁-C₆ alkyl;

[0008] R³ is H, C₁-C₆ alkyl, Cl, F, CF₃, OCF₂H, OCF₃, OH or C₁-C₆alkoxy;

[0009] R⁴ is H, C₁-C₆ alkyl, C₁-C₆alkoxy, cycloalkyl, alkenyl, aryl,benzyl, heteroaryl, heterocycloalkyl, arylNH—, heteroarylNH—,cycloalkylNH—, N(R²)₂, or NR²aryl, said alkyl, alkoxy, cycloalkyl,alkenyl, phenyl or heteroaryl optionally substituted with one to threeX;

[0010] R⁵ is H or C₁-C₆ alkyl;

[0011] R⁶ is H or C₁-C₆ alkyl; or

[0012] R⁵ and R ⁶taken together with the carbon atom form a carbonylgroup;

[0013] L¹ is C₁-C₆ alkylene, C₂-C₆alkenylene, C(R²)₂,

[0014]  —CHOR²—, NOR⁵—, —SO₂—, —SO—, —S—, —O—, —NR²—, —C(O)NR²—,—NR²C(O)—, —CHCF₃— or —CF₂—;

[0015] L² is a covalent bond, C₁-C₆ alkylene, —C(R²)₂—,

[0016]  —CHOR²—, —C(R²)OH, NOR⁵—, —SO₂—, —NR²SO₂—, —SO—, —S—, —O—,—SO₂NR²—, —N(R²)—, —C(O)NR²— or —NR²C(O)—;

[0017] X is the same or different, and is independently selected from H,halogen, CF₃, CN, OCF₂H, OCF₂CF₃, OCF₃, OR², C₁-C₆ alkyl, cycloalkyl,cycloalkoxy, C₁-C₆ alkoxy, alkoxyC₁-C₆alkoxy, O-cycloalkyl,cycloalkylamino, cycloalkylalkoxy, heteroalkyl, —OSO₂R², —COOR²,—CON(R²)₂, NHR², arylNH—, N(R²)₂, or NR² aryl;

[0018] Y is a covalent bond, —CH₂—, —SO₂—, or

[0019] Z is a covalent bond, —CH₂—, —SO₂— or

[0020] Y, R¹, Z and R² can be taken together with the nitrogen atom toform a heterocycloalkyl; with the proviso that if Y is a covalent bond,R¹ cannot form a N—N bond with the nitrogen atom; and

[0021] n is an integer of 0 to 4.

[0022] Cannabinoid receptor ligands according to the present inventionhave anti-inflammatory activity and/or immunomodulatory activity and areuseful in the treatment of various medical conditions including, e.g.,cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupuserythematosus, multiple sclerosis, glaucoma, diabetes, osteoporosis,renal ischemia, myocardial infarction, cerebral stroke, cerebralischemia, nephritis, hepatitis, glomerulonephritis, cryptogenicfibrosing aveolitis, psoriasis, atopic dermatitis, vasculitis, allergy,seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease,reversible airway obstruction, adult respiratory distress syndrome,asthma, chronic obstructive pulmonary disease (COPD) or bronchitis. Itis contemplated that a compound of this invention may be useful intreating more than one of the diseases listed.

[0023] Additionally, a compound of the present invention may beco-administered or used in combination with disease-modifyingantirheumatic drugs (DMARDS) such as methotrexate, azathioprineleflunomide, penicillamine, gold salts, mycophenolate mofetil,cyclophosphamide and other similar drugs. They may also beco-administered with or used in combination with NSAIDS such aspiroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2selective inhibitors such as Vioxx® and Celebrex®; COX-1 inhibitors suchas Feldene; immunosuppressives such as steroids, cyclosporine,Tacrolimus, rapamycin, muromonab-CD3 (OKT3), Basiliximab and the like;biological response modifiers (BRMs) such as Enbrel, Remicade, IL-1antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules andthe like; and other anti-inflammatory agents such as p38 kinaseinhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptorantagonists, Thalidomide and other small molecule inhibitors ofpro-inflammatory cytokine production. They may also be co-administeredwith or used in combination with H1 antagonists such as Claritin,Clarinex, Zyrtec, Allegra, Benadryl, and other H1 antagonists. Otherdrugs that the compounds of the invention may be co-administered or usedin combination with include Anaprox, Arava, Arthrotec, Azulfidine,Aspirin, Cataflam, Celestone Soluspan, Clinoril, Cortone Acetate,Cuprimine, Daypro, Decadron, Depen, Depo-Medrol, Disalcid, Dolobid,Naprosyn, Gengraf, Hydrocortone, Imuran, Indocin, Lodine, Motrin,Myochrysine, Nalfon, Naprelan, Neoral, Orudis, Oruvail, Pediapred,Plaquenil, Prelone, Relafen, Solu-Medrol, Tolectin, Trilisate andVolataren. These include any formulations of the above-named drugs.

[0024] For the treatment of multiple sclerosis, the compounds of theinvention may be co-administered or used in combination with Avonex,Betaseron, Rebif and Copaxone. These include any formulations of theabove-named drugs.

[0025] For the treatment of psoriasis, the compounds of the inventionmay be co-administered or used in combination with steroids,methotrexate, cyclosporin, Xanelin, Amivere, Vitamin D analogs, topicalretinoids, anti-TNF-α compounds and other drugs indicated for thiscondition. These include any formulations of the above-named drugs.

[0026] For the treatment of asthma, the compounds of the invention maybe co-administered or used in combination with Singulair, Accolate,Albuterol, and other drugs indicated for this disease. These include anyformulations of the above-named drugs.

[0027] For the treatment of inflammatory bowel disease or Crohn'sdisease, the compounds of the invention may be co-administered or usedin combination with sulfasalazine, budesonide, mesalamine and otherdrugs indicated for these diseases. These include any formulations ofthe above-named drugs.

[0028] In another aspect, the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I in a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

[0029] Unless otherwise defined, the following definitions shall applythroughout the specification and claims.

[0030] When any variable (e.g., R²) occurs more than one time in anyconstituent, its definition in each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

[0031] “Alkyl” means straight or branched alkyl chains of 1 to 12 carbonatoms. The term includes the isomers thereof such as isopropyl,isobutyl, sec-butyl, etc.

[0032] “Haloalkyl” means alkyl having 1 or more halo atoms.

[0033] “Heteroalkyl” means straight or branched alkyl chain comprised offrom 1 to 12 carbon atoms and 1 or more heteroatoms independentlyselected from the group consisting of N, O and S.

[0034] “Cycloalkyl” as used herein refers to an aliphatic ring systemhaving 3 to 10 carbon atoms and 1 to 3 rings, including, but not limitedto cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl amongothers.

[0035] “Heterocycloalkyl” means cycloalkyl containing one or moreheteroatoms.

[0036] “Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising from 6 to 14 carbon atoms. Non-limiting examples includephenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

[0037] “Arylalkyl” means a group in which the aryl and alkyl are aspreviously desecribed. Non-limiting examples of suitable arylalkylgroups include benzyl, 2-phenethyl and naphthlenylmethyl. The bond tothe parent moiety is through the alkyl.

[0038] “Heteroaryl” means a single ring or benzofused heteroaromaticgroup of 5 to 10 atoms comprised of 1 to 9 carbon atoms and 1 or moreheteroatoms independently selected from the group consisting of N, O andS. N-oxides of the ring nitrogens are also included, as well ascompounds wherein a ring nitrogen is substituted by a C₁-C₆ alkyl groupto form a quaternary amine. Examples of single-ring heteroaryl groupsare pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl,thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examplesof benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl,phthalazinyl, benzothienyl (i.e., thionaphthenyl), benzimidazolyl,benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomersare contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.

[0039] “Alkoxy” means an alkyl radical attached by an oxygen, i.e.,alkoxy groups having 1 to 9 carbon atoms.

[0040] “Alkenyl” means straight or branched chains of carbon atomshaving one or more double bonds in the chain, conjugated orunconjugated.

[0041] “Oxime” means a CH(:NOH) radical containing moiety.

[0042] “Halogen”, “halogenated” or “halo” refers to fluorine, chlorine,bromine or iodine radicals.

[0043] The term “prodrug,” as used herein, represents compounds whichare rapidly transformed in vivo to the parent compound of the aboveformula, for example, by hydrolysis in blood. A thorough discussion isprovided in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

[0044] Linker groups such as L¹, L², Y and Z are divalent.

[0045] In a preferred group of compounds of formula I,

[0046] L¹ is —SO₂—, —CH₂—, —CHCH₃—,

[0047]  —C═NOR²—, —C(CH₃)₂—, —CHOH—, —O—, —S— or —S═O;

[0048] L² is —SO₂—,

[0049]  —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,

[0050]  —NH—, —O—, —NHSO₂—, —NHC(O)— or

[0051] R¹ is H, —CH₃NH₂, —CH₂CF₃, —NHC₃H₇, —NHC₂H₆, —NHC₄H₉, C₁-C₆alkyl,—CF₃, —CH(CH₃)₂, thiophenyl, morpholinyl, cyclopropanyl, benzyl,naphthyl, C(CH₃)₃, NHphenyl, 3,5-difluorophenyl, phenyl, N-cyclopentylor N(CH₃)₂;

[0052] R² is H or CH₃;

[0053] R⁴ is furanyl, pyridyl, pyrimidyl, thiophenyl, quinolyl,t-butoxy, alkoxyl, cyclohexyl, phenyl, tolyl, C₃H₇, dimethylpyrimdyl,trifluoromethoxyphenyl, morpholinylphenyl or CH₃; with the proviso thatwhen R⁴ is t-butoxy, L² must be

[0054]  —CH₂—, —CHCH₃—, —C(CH₃)₂— or

[0055]  all of the above optionally substituted with one to threesubstituents, which are the same or different and are independentlyselected from X;

[0056] R⁵ and R⁶ are independently H or CH₃;

[0057] X is H, Cl, CF₃, OCH₃, OCF₃, OCF₂H, CH₃ or C₁-C₆ cycloalkyl;

[0058] Y is —SO₂— or

[0059] Z is a covalent bond; or

[0060] R¹, Y, R² and Z taken together with the nitrogen atom form amorpholinyl group.

[0061] In a more preferred embodiment of the invention,

[0062] L¹ is —SO₂— or —CH₂—;

[0063] L² is —SO₂—;

[0064] R¹ is CH₃ or CF₃; and

[0065] R⁴ is phenyl, pyrimidyl or pyridyl, said phenyl, pyrimidyl orpyridyl groups optionally substituted with one to three substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, OH, CF₃ and halogen.

[0066] More preferably, the phenyl is substituted with OCH₃ or halogenselected from fluorine and chlorine.

[0067] Compounds of the invention may have at least one asymmetricalcarbon atom and therefore all isomers, including diastereomers androtational isomers are contemplated as being part of this invention. Theinvention includes (+)- and (−)-isomers in both pure form and inadmixture, including racemic mixtures. Isomers can be prepared usingconventional techniques, either by reacting optionally pure or opticallyenriched starting materials or by separating isomers of a compound offormula I. Those skilled in the art will appreciate that for somecompounds of formula I, one isomer may show greater pharmacologicalactivity that other isomers.

[0068] Compounds of formula I can exist in unsolvated and solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for purposes of thisinvention.

[0069] Compounds of the invention with a basic group can formpharmaceutically acceptable salts with organic and inorganic acids.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineraland carboxylic acids well known to those in the art. The salt isprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt. The free base form may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous sodium bicarbonate. The free base formdiffers from its respective salt form somewhat in certain physicalproperties, such as solubility in polar solvents, but the salt isotherwise equivalent to its respective free base forms for purposes ofthe invention.

[0070] Certain compounds of the invention are acidic (e.g., compoundswhere R² is a hydrogen covalently bonded to N). Acidic compoundsaccording to the present invention can form pharmaceutically acceptablesalts with inorganic and organic bases. Examples of such salts are thesodium, potassium, calcium, aluminum, magnesium, zinc, lithium, gold andsilver salts. Also included are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine, piperazines and other amines.

[0071] Compounds of the present invention are generally prepared byprocesses known in the art, for example by the processes describedbelow.

[0072] The following abbreviations are used in the procedures andschemes: aqueous (aq), anhydrous (anhyd), n-butyllithium (n-BuLi),dibromodimethylhydantoin (DBDMH), diisopropylethylamine (DIPEA), diethylether (Et₂O), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl),ethanol (EtOH), ethyl acetate (EtOAc), 2-propanol (IPA), leaving group(LG), lithium hexamethyidisilazide (LHMDS), meta-chloroperoxybenzoicacid (MCPBA), methanesulfonic acid (MsOH), methanesulfonyl chloride(MsCl), N-iodosuccinamide (NIS), preparative thin layer chromatographyon Merck-silica plates (PTLC), phenyl (Ph), pyridinium chlorochromate(PCC), pyridine (Py), trifluoroacetic anhydride (TFAA), triflicanhydride (Tf₂O), tetrahydrofuran (THF), silica gel chromatography(sgc), thin layer chromatography (TLC), room temperature (rt), hours(h), minutes (min), molar (M), pounds per square inch (psi), andsaturated aqueous sodium chloride solution (brine).

[0073] Description of Reactions—General Scheme I

[0074] In step 1, trifluoroacetic anhydride is dissolved in a suitableinert solvent such as methylene chloride and reacted with a benzyl amineat room temperature for 1-5 hr. MsOH (2 eq) is added followed by DBDMHand the reaction mixture is stirred overnight at room temperature andsubjected to aqueous work up. The crude product is recrystallized from amixture of Et₂O and hexanes or purified via chromatography.

[0075] In step 2, the product of step 1 is dissolved in THF, cooled in adry ice/IPA bath and treated with methyllithium then n-BuLi. Theresulting dianion may be trapped with a sulfonyl fluoride or adisulfide. If a disulfide is the trapping agent, the resulting productis oxidized with MCPBA in CH₂Cl₂ at room temperature for 1-6 h. Theproduct may be purified via chromatography or crystallization.

[0076] In step 3, the product of step 2 is dissolved in THF and treatedwith n-BuLi at −78° C. to form a dianion that is trapped with a suitableelectrophile.

[0077] Alternatively, in step 3 the product of step 2 is dissolved inTHF treated with n-BuLi at −78° C. to form a dianion which is trappedwith iodine to provide the iodo substituted product. The product may bepurified via sgc or crystallization. The iodo product can be convertedto a similar product by nucleophilic aromatic substitution with avariety of nucleophiles, including amines, alcohols, and thiols.

[0078] In step 4, the product of step 3 is dissolved in a suitablesolvent such as dioxane, ethanol, methanol or THF and an alkali metalhydroxide or carbonate such as lithium hydroxide or potassium carbonateis added either as an aqueous solution or as a solid. The reactionmixture is stirred at room temperature for 0.5-24 h. The product may bepurified via sgc or crystallization.

[0079] In step 5, a combination of the product of step 4 and a tertiaryamine base was dissolved in a suitable solvent such as CH₂Cl₂ ordioxane, at room temperature, cooled, and a suitable electrophile isadded. The reaction mixture is stirred between −78° C. and 100° C. for0.5 to 48 h. The product may be purified via sgc or crystallization.

[0080] In step 6, the product of step 5 is dissolved in a suitable inertsolvent such as THF or CH₂Cl₂ and treated with a suitable base such asNaH or triethylamine. An electrophile is added and the reaction mixtureis stirred between 0° C. and 100° C. for 0.5 to 48 h. The product may bepurified via sgc or crystallization.

[0081] Description of Reactions—General Scheme II

[0082] In step 1, trifluoroacetic anhydride is dissolved in a suitableinert solvent such as methylene chloride and treated with a benzyl amineat ambient temperature, then stirred for 1-5 h. Methanesulfonic acid (2eq) is added followed by dibromodimethylhydantoin and the reactionmixture is stirred overnight at rt and subjected to aqueous work up. Theproduct may be purified by chromatography or crystallization.

[0083] In step 2, the product of step 1 is dissolved in THF, cooled in adry ice/acetone bath (−78° C.) and treated with methyllithium, thenn-BuLi. The dianion is then treated with a THF solution containing thealdehyde (i). The resulting mixture is warmed to rt and stirred for 10h. The product is purified by chromatography.

[0084] In step 3, the alcohol product from step 2 is dissolved inmethylene chloride and treated with ten fold excess of triethylsilanefollowed by a slight excess of boron trifluoride etherate. The resultingmixture is stirred at room temperature for 4 h, and purified bychromatography.

[0085] In step 4, the product of step 3 is dissolved in a suitablesolvent such as dioxane, ethanol, or THF and an alkali metal hydroxidesuch as lithium hydroxide is added either as an aqueous solution or as asolid. The reaction mixture is stirred at rt for 0.5-24 h.

[0086] In step 5, the product of step 4 is dissolved in a mixture of asuitable inert solvent such as CH₂Cl₂ or dioxane and a tertiary aminebase, and a suitable electrophile is added. The reaction mixture isstirred between −78° C. and 100° C. for 0.5 to 48 h.

[0087] In step 6, the product of step 5 is dissolved in a suitable inertsolvent such as THF or CH₂Cl₂ and treated with a suitable base such asNaH or triethylamine. An electrophile is added and the reaction mixtureis stirred between 0° C. and 100° C. for 0.5 to 48 h.

[0088] The aldehyde (i) used in step 2 was prepared by one of thefollowing two procedures; 1) Regioselective ortho lithiation of a4-substituted benzaldehyde, and quenching with a substituted phenyldisulfide followed by oxidation with metachloroperoxybenzoic acid to thesulfone. 2) Base promoted displacement of fluoride from anortho-fluorobenzaldehyde by a thiophenol, phenol, or aniline.

[0089] Description of Reactions—General Scheme III

[0090] In step 1 the secondary alcohol, the product of Step 2 in SchemeII is oxidized with PCC, in a suitable inert solvent such as CH₂Cl₂, tothe carbonyl by stirring at rt for 18 h. In step 2, the ketone istreated with the ylide obtained by base treatment of driedmethyltriphenylphosphonium bromide, providing the exo methylene product.In step 3 the trifluoroacetamide group can be hydrolyzed with base andreacted with a variety of acylating, sulfonylating, alkylating and otherelectrophilic reagents.

[0091] The ketone product can be treated with hydroxylaminehydrochloride in pyridine and heated at 80° C. for 24 h. The mixture wascooled to room temperature and the solvent removed under reducedpressure. Upon workup and purification, the oxime is obtained.

[0092] Description of Reactions—General Scheme IV

[0093] In step 1, 2-bromo-4-chlorophenol and a 4-fluorobenzonitrile aredissolved in a polar aprotic solvent such as DMA in the presence of asuitable base such as potassium hydroxide. The reaction mixture isheated for 0.5-7 days. Preferred temperatures are greater than 60° C.The reaction mixture is diluted with a suitable extraction solvent suchas diethyl ether and washed with water. The solvents are removed and theproduct is purified via sgc.

[0094] In step 2, the product of step 1 is dissolved in a solution ofdiborane in THF. The reaction is stirred at reflux for 1-24 h thenquenched with water and partitioned between EtOAc and aq NaOH. Thesolvents are evaporated and the product is purified by formation of theHCl salt in diethyl ether.

[0095] In step 3, the product of step 2 is suspended in CH₂Cl₂ and asuitable base such as triethylamine is added. The reaction mixture iscooled, and TFAA is added. The reaction mixture is stirred from 0.5 to 8h, then subjected to aqueous workup. The crude product is purified bysgc.

[0096] In step 4, the product of step 3 is dissolved in THF and treatedwith methyl lithium, then n-BuLi at −78° C. to form a dianion that istrapped with a suitable electrophile. The reaction mixture is quenchedwith a suitable proton source such as aq NH₄Cl or phosphate buffer thenextracted with EtOAc. The product may be purified via sgc orcrystallization.

[0097] In step 5, the product of step 4 is dissolved in a suitablesolvent such as dioxane, ethanol, or THF and an alkali metal hydroxidesuch as lithium hydroxide is added either as an aqueous solution or as asolid. The reaction mixture is stirred at rt for 0.5-24 h.

[0098] In step 6, the product of step 5 is dissolved in a mixture of asuitable inert solvent such as CH₂Cl₂ or dioxane and a tertiary aminebase, and a suitable electrophile is added. The reaction mixture isstirred between −78° C. and 100° C. for 0.5 to 48 h.

[0099] In step 7, the product of step 6 is dissolved in a suitable inertsolvent such as THF or CH₂Cl₂ and treated with a suitable base such asNaH or triethylamine. An electrophile is added and the reaction mixtureis stirred between 0° C. and 100° C. for 0.5 to 48 h.

[0100] Description of Reactions—General Scheme V

[0101] In step 1, 1-chloro-4-fluorobenzene is dissolved in anhyd THF andtreated with n-BuLi at −78° C. to form an anion that is trapped with asuitable electrophile. The product may be purified via sgc orcrystallization.

[0102] In step 2, the product of step 1 is dissolved in a suitable polarsolvent such as acetonitrile or DMA. A benzoic acid containing anucleophilic moiety such as an OH, NHR, or SH is added, and two or moreequivalents of a suitable base such as potassium hydroxide or sodiumhydride is added. The reaction mixture may be stirred for 1-24 h attemperatures ranging between 0° C. and 150° C. The reaction mixture ispartitioned between water and a suitable solvent such as EtOAc. Theproduct may be purified via sgc or crystallization.

[0103] In step 3, the product of step 2 is dissolved in CH₂Cl₂.Pentafluorophenol and EDCl are added. The reaction mixture is stirred atrt for 0.5-24 h then partitioned between water and CH₂Cl₂. The solventsare evaporated. The product may be purified via sgc or crystallization.

[0104] In step 4, the product of step 3 is dissolved in a suitablesolvent such as CH₂Cl₂. An amine base such as DIPEA or triethylamine isadded, followed by a primary or secondary amine. The reaction mixturemay be stirred for 1-24 h at rt. The reaction mixture is then subjectedto aqueous workup and isolation and the product is purified via sgc.

[0105] In step 5, if the nucleophilic moiety in step 2 containsoxidizable functionality, the product of step 4 is dissolved in asuitable solvent such as CH₂Cl₂ and MCPBA is added. The reaction mixturemay be stirred for 0.5-48 h then partitioned between a suitable solventsuch as CH₂Cl₂ or EtOAc and an aqueous base such as Na₂CO₃. The solventis evaporated and the product is purified via sgc.

[0106] Description of Reactions—General Scheme VI

[0107] In step 1, trifluoroacetic anhydride is dissolved in a suitableinert solvent such as methylene chloride and reacted with a benzyl amineat rt for 1-5 h. Methanesulfonic acid (2 eq) is added followed byN-iodosuccinamide. The reaction mixture is stirred overnight at rt, thensubjected to aqueous work up. The crude product is recrystallized fromisopropanol and water.

[0108] In step 2, CuCl is dissolved in glacial acetic acid. The flask iscooled to 0° C. and SO₂ gas is bubbled in with stirring for 40 min. In aseparate flask 2-fluoro-4-chloroaniline is dissolved in glacial aceticacid and concentrated HCl. The resulting solution is cooled to 0° C. andtreated with an aqueous solution of NaNO₂. The reaction mixture isstirred for 30 min at 0° C. and the contents are added to the flaskcontaining the SO₂ solution causing vigorous gas evolution. The reactionis then allowed to warm to rt. The product is isolated by pouring thereaction mixture onto chipped ice, then filtering the resulting solid.

[0109] In step 3, the product of step 2 is dissolved in acetone. Anaqueous solution of KF (2 eq) is added and the reaction mixture isstirred for 12-24 h at rt. The reaction mixture is extracted with asuitable solvent such as CH₂Cl₂ or Et₂O and the solvent is evaporated toafford the product.

[0110] In step 4, the product of step 1 is dissolved in THF and TMEDA isadded. The flask is placed under N₂ blanket, and cooled to 0° C. Asolution of isopropyl magnesium chloride in THF is added and thereaction mixture is stirred for 1-4 h. The resulting solution is addedto a flask containing the product of step 3 that was cooled with anice-water bath. The reaction mixture is stirred for 1-3 h. The reactionis quenched with aqueous NH₄Cl and extracted with EtOAc. Afterevaporation of the solvent, the crude product is purified via sgc.

[0111] In step 5, the product of step 4 is dissolved in a suitablesolvent such as dioxane, ethanol, or THF and an alkali metal hydroxidesuch as lithium hydroxide is added either as an aqueous solution or as asolid. The reaction mixture is stirred at rt for 0.5-24 h. The productmay be purified via sgc or crystallization.

[0112] In step 6, the product of step 5 is dissolved in a suitable inertsolvent such as CH₂Cl₂ or acetonitrile and a tertiary amine base, and atriflic anhydride is added. The reaction mixture is stirred between −78°C. and rt for 0.5 to 48 h. The product may be purified via sgc orcrystallization.

[0113] In step 7, the product of step 6 is dissolved in a suitable inertsolvent such as dioxane and a thiol is added. A base such as sodiumhydride, sodium hydroxide, or NaHMDS is added and the reaction mixtureis stirred at a suitable temperature between 50° C. and 100° C. for 4-24h. The reaction mixture is quenched with water and extracted with asuitable solvent. The solvents are evaporated and the crude product ispurified via sgc.

[0114] In step 8, the product of step 7 is dissolved in a suitable inertsolvent such as CH₂Cl₂. Na₂HPO₄ and urea hydrogen peroxide complex isadded, followed by TFAA. The reaction mixture is refluxed for 4-16 h,then partitioned between water and CH₂Cl₂. The solvents are evaporatedand the crude product is purified via sgc.

[0115] Those skilled in the art will appreciate that similar reactionsto those described in the above schemes may be carried out on othercompounds of formula I as long as substituents present would not besusceptible to the reaction conditions described. Starting materials forthe above processes are either commercially available, known in the art,or prepared by procedures well known in the art. Exemplary compounds offormula 1 are set forth below in Table I. CB means covalent bond. TABLEI R¹ R² R³ R⁴ R⁵ R⁶ L¹ L² X Y Z A CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB B CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB C CH₃ H H

H CH₃ SO₂ SO₂ OCF₂H SO₂ CB D CH₃ H H t-butoxy H CH₃ SO₂ CO OCH₃ SO₂ CB ECH₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB F CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB G CH₃ H H

H CH₃ SO₂ SO₂ CH₃ SO₂ CB H CF₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB I CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB J CH₃ H H

H CH₃ SO₂ SO₂ OCF₃ SO₂ CB K CH₃ H H t-butoxy H CH₃ SO₂ C═O OCF₂H SO₂ CBL CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB M CH₃ H H

H H SO₂ SO₂ OCH₃ SO₂ CB N CH₃ H H

H H CH₂ SO₂ OCH₃ SO₂ CB O CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB P CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB Q CH₃ H H

H CH₃ SO₂ SO₂ CH₃ SO₂ CB R CF₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB S CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB T CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB U CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB V CF₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB W CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB X CF₃ H H

CH₃ CH₃ CH₂ SO₂ OCF₃ SO₂ CB Y C₄H₉ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB Z CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB AA CH₃ H H C₃H₇ H CH₃ SO₂ SO₂ OCH₃ SO₂ CB ABCH₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB AC CH₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB AE CF₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB AF CH₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB AG CF₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB AH CF₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB Al CH₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB AK CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AM CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AO CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AQ CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AR CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AS CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AT N(CH₃)₂ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AU CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AV CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AW CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB AX CH₃ H H C₃H₇ H CH₃ SO₂ SO₂ Cl SO₂ CB AY CF₃ HH

CH₃ CH₃ SO₂ SO₂ Cl

CB AZ CF3 H H

CH₃ CH₃ SO₂ SO₂ Cl SO₂ CB BA CH₃ H H

H CH₃ SO₂ SO₂ OCF₃ SO₂ CB BB CH₃ H H

H CH₃ SO₂ SO₂ OCF₃ SO₂ CB BC CH₃ H H

H CH₃ SO₂ SO₂ OCF₃ SO₂ CB BD CF₃ H H

H CH₃ SO₂ SO₂ OCF₃ SO₂ CB BG CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB BH CF₃ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB BJ CF₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB BN CF₃ H H C₃H₇ H CH₃ SO₂ SO₂ OCH₃ C═O CB BOCF₃ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB BP NHC₃H₇ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB BR CF₃ H H

CH₃ CH₃ SO₂ SO₂ OCH₃ C═O CB BS CH₃ H H

CH₃ CH₃ SO₂ SO₂ OCH₃ SO₂ CB BT CH₃ CH₃ H

CH₃ CH₃ SO₂ SO₂ OCH₃ SO₂ CB BU CH₃ H H

H H SO₂ SO₂ OCH₃ SO₂ CB BV CH₃ CH₃ H

H H SO₂ SO₂ OCH₃ SO₂ CB BW CF₃ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB BX CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB BY CH₃ CH₃ H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB BZ CF₃ H H

H CH₃ SO₂ SO₂ CH₃ SO₂ CB CA CF₃ H H

H CH₃ SO₂ SO₂ CH₃ SO₂ CB CB CH₃ H H

H CH₃ SO₂ SO₂ CH₃ SO₂ CB CC CF₃ H H C₃H₇ H CH₃ SO₂ SO₂ Cl C═O CB CD CH₃H H

H CH₃ SO₂ SO₂ Cl SO₂ CB CE CH₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB CF —CH(CH₃)₂ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CG NH₂ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CH C₄H₉ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB Cl —CHCF₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CJ

H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CK

H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CL

H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CM

H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB CN CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CO

H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CP C₃H₇ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CQ

H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CR

H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CS CH₃ H H

H CH₃ SO₂ SO₂ Cl C═O CB CT NH—(CH₂)₂—CH₃ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CU

H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB CV CF₃ H H

H CH₃ SO₂ C═O OH C═O CB CW CH₃ H H

H CH₃ SO₂ SO₂ OH SO₂ CB CX CH₃ H H

H CH₃ SO₂ SO₂ OH SO₂ CB CZ CF₃ H H

H CH₃ SO₂ SO₂ OCF₂H C═O CB DA CH₃ H H

H CH₃ SO₂ SO₂ OCF₂H SO₂ CB DC CF₃ H H

H CH₃ SO₂ C═O OCH₃ SO₂ CB DD CF₃ H H

H CH₃ SO₂ C═O OCH₃ C═O CB DE

H H

H CH₃ SO₂ C═O OCH₃ C═O CB DF CH₃ H H

H CH₃ SO₂ C═O Cl SO₂ CB DG CF₃ H H

H CH₃ SO₂ C═O Cl SO₂ CB DH CH₃ H H

H CH₃ SO₂ CH₂ Cl SO₂ CB DI CH₃ H H

H CH₃ SO₂ C═O Cl SO₂ CB DJ CH₃ H H

H CH₃ SO₂ CH₂ Cl SO₂ CB DK CH₃ H H

H CH₃ SO₂ C═O Cl SO₂ CB DL CH₃ H H

H CH₃ SO₂ C═CH₂ Cl SO₂ CB DM CF₃ H H

H CH₃ SO₂

Cl C═O CB DN CF₃ H H

H CH₃ SO₂ C═O Cl C═O CB DP CF₃ CH₃ H

H CH₃ SO₂ C═CH₂ Cl C═O CB DQ CH₃ H H

CH₃ CH₃ SO₂ C═O Cl SO₂ CB DR CH₃ H H

H CH₃ SO₂ NH Cl SO₂ CB DS CF₃ H H

H CH₃ SO₂ O Cl C═O CB DU CH₃ H H

H CH₃ CH₂ SO₂ OCH₃ SO₂ CB DV CH₃ H H

H CH₃ CH₂ SO₂ Cl SO₂ CB DW CF₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB DX CH₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB DY CF₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB DZ CH₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB EA CF₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB EC CH₃ H H

H CH₃ CH₂ SO₂ CF₃ SO₂ CB ED CF₃ H H

H CH₃ CH₂ SO₂ OCF₃ C═O CB EE CH₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EG CH₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EH CF₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EI CF₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EJ CH₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EK CF₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EL CH₃ H H

H H CH₂ SO₂ OCH₃ SO₂ CB EN CF₃ H H

CH₃ CH₃ CH₂ SO₂ OCF₃ C═O CB EP CH₃ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB EU CH₃ H H

H CH₃ C═O SO₂ OCF₃ SO₂ CB EV CF₃ H H

H CH₃ C═O SO₂ OCH₃ SO₂ CB EW CF₃ H H

H CH₃ C═O O H C═O CB EX CF₃ H H

H CH₃ C═O O H C═O CB EY CF₃ H H

H CH₃ C═O O Cl C═O CB EZ CH₃ H H

H CH₃ C═O SO₂ OCF₃ C═O CB FA CF₃ H H

H CH₃ C═O NHSO₂ H C═O CB FB CF₃ H H

H CH₃ C═O NHCO H C═O CB FC CF₃ H H

H CH₃ C═CH₂ SO₂ OCF₃ C═O CB FD CH₃ H H

H CH₃ C═CH₂ SO₂ OCF₃ SO₂ CB FE CF₃ H H

H CH₃ C═O SO₂ OCF₃ SO₂ CB FF CH₃ H H

H CH₃ C═NOH SO₂ OCF₃ SO₂ CB FG CH₃ H H

H CH₃ C(CH₃)₂ SO₂ Cl SO₂ CB FH CF₃ H H

H H C═O SO₂ OCH₃ C═O CB FI CH₃ H H

H H O SO₂ Cl SO₂ CB FJ *R¹, Y, Z and R² combine to form morpholinyl * H

—

S SO₂ Cl * * FK H CH₃ H

—

S═O SO₂ Cl CB CB FL H CH₃ H

—

SO₂ SO₂ Cl CB CB FM *R¹, Y, Z and R² combine to form morpholinyl * H

—

SO₂ SO₂ Cl * * FN CH₃ CH₃ H

—

S SO₂ Cl CB CB FO H H H

—

S SO₂ Cl CB CB FP CH₃ CH₃ H

—

SO₂ SO₂ Cl CB CB FQ H H H

—

SO₂ SO₂ Cl CB CB FR CH₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB FS CH₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB FT CH₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB FU CF₃ H H

H CH₃ SO₂ SO₂ H C═O CB FV CH₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB FW CH₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB FX CF₃ H H

H CH₃ SO₂ SO₂ H C═O CB FY CF₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB FZ CF₃ H H

H CH₃ SO₂ SO₂ H SO₂ CB GA CH₃ H H

H CH₃ CH₂ SO₂ OCF₃ C═O CB GD

H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB GF NHC₂H₆ H H

H CH₃ CH₂ SO₂ OCF₃ SO₂ CB GG CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB GH CF₃ H H

H CH₃ SO₂ SO₂ CF₃ SO₂ CB GI CF₃ H H

H CH₃ SO₂ SO₂ Cl SO₂ CB GJ CF₃ H H

H CH₃ SO₂ SO₂ OCH₃ SO₂ CB GK CF₃ H H

H CH₃ SO₂ C═O OCH₃ SO₂ CB GL CF₃ H H

H CH₃ SO₂ SO₂ OH SO₂ CB GM CF₃ H H

H CH₃ SO₂ SO₂ OCH (CH₃)₂ SO₂ CB GN CF₃ H H

H CH₃ SO₂ SO₂

SO₂ CB GO CF₃ H H

H CH₃ SO₂ SO₂ OCH₃ C═O CB

[0116] In a preferred embodiment, there are disclosed compounds of theformula

[0117] a prodrug thereof, or a pharmaceutically acceptable salt of thecompound or of said prodrug; wherein X, R¹ and R⁴ are as shown in thetable below: Example X R¹ R⁴ A OCH₃ CH₃

C OCF₂H CH₃

G CH₃ CH₃

L Cl CH₃

R CF₃ CF₃

S Cl CF₃

AB CF₃ CH₃

AT Cl N(CH₃)₂

BA OCF₃ CH₃

BD OCF₃ CF₃

BZ CH₃ CF₃

CD Cl CH₃

FS H CH₃

FY H CF₃

GG Cl CF₃

GH CF₃ CF₃

XXIX

CF₃

XXX

CF₃

XXXI

CF₃

XXXII CN CF₃

XXXIII NH₂ CF₃

XXXIV

CF₃

XXXVI Cl CF₃

XXXVII

CF₃

XXXVIII CN CF₃

XXXIX —CONH₂ CF₃

XXXX —OCH₃ CF₃

XXXXI —OH CF₃

XXXXII

CF₃

XXXXIII

CF₃

XXXXIV

CF₃

XXXXV

CF₃

XXXXXV OCH₃ CF₃

XXXXXVI

CH₃

[0118] In another preferred embodiment, there are disclosed compounds ofthe formula

[0119] a prodrug thereof, or a pharmaceutically acceptable salt of thecompound or of said prodrug; wherein X, Y—R¹ and R⁴ are as shown in thetable below: Example X Y—R¹ R⁴ XXXXVI

XXXXVII

XXXXVIII

XXXXIX

XXXXXI —OCH₃

XXXXXII —OCH₃

XXXXXIII —OCH₃

[0120] Compound A: ¹H NMR (300 MHz, CDCl₃) 1.54 (d, J=6.9 Hz 3H), 2.67(s, 3H), 4.72 (q, J=5 Hz 1H), 4.86 (br. d, J=5 Hz,1 H, NH), 7.08-8.42(m, 11H).

[0121] Compound C: ¹H NMR (400 MHz, CDCl₃) 1.51 (d, J=7.2 Hz 3H), 2.67(s, 3H), 4.702 (q, J=6.8 Hz 1H), 5.05 (br. d, J=6.4 Hz,1H, NH), 6.71 (t,J=71.6 Hz, CF2H) 7.07-8.47 (m, 11H).

[0122] Compound G: ¹H NMR (300 MHz, CDCl₃) 8.43-8.41 (m, 1H), 8.36 (d, 8Hz, 1H), 8.28-8.22 (m, 1H), 7.96-7.92 (m, 2H), 7.69-7.60 (m, 2H),7.52-7.47 (m, 2H), 7.43-7.37 (m, 1H), 7.13-7.06 (m, 1H), 4.76-4.70 (m,2H), 2.68 (s, 3H), 2.59 (s, 3H), 1.41 (d, 7 Hz, 3H).

[0123] Compound L: ¹H NMR (300 MHz, CDCl₃) 8.61-5.97 (m, 2H), 8.40 (d, 8Hz, 1H), 8.24-8.21 (m, 1H), 7.96 (d, 8 Hz, 2H), 7.86-7.83 (m, 1H),7.70-7.63 (m, 1H), 7.52 (d, 8 Hz, 2H), 7.46-7.40 (m, 1H), 7.18-7.12 (m,1H), 4.80-4.70 (m, 1H), 2.71 (s, 3H), 1.56 (d, 7 Hz, 3H).

[0124] Compound R: ¹H NMR (300 MHz, CDCl₃) 8.89-8.87 (m, 1H), 8.58 (d, 8Hz, 1H), 8.32-8.25 (m, 1H), 8.15-8.11 (m, 1H), 8.03-7.98 (m, 2H),7.71-7.63 (m, 1H), 7.52-7.48 (m, 2H), 7.47-7.41 (m, 1H), 7.16-7.09 (m,1H), 5.62 (d, 8 Hz, 1H), 4.90-4.80 (m, 1H), 1.63 (d, 7 Hz, 3H).

[0125] Compound S: ¹H NMR (300 MHz, CDCl₃) 8.61-8.59 (m, 1H), 8.39 (d, 8Hz, 1H), 8.29-8.24 (m, 1H), 7.99 (d, 8 Hz, 2H), 7.86-7.82 (m, 1H),7.67-7.62 (m, 1H), 7.49 (d, 8 Hz, 1H), 7.46-7.40 (m, 1H), 7.16-7.10 (m,1H), 4.89-4.84 (m, 1H), 1.65 (d, 6 Hz, 1H).

[0126] Compound AB: ¹H NMR (300 MHz, CDCl₃) 8.88-8.86 (m, 1H), 8.62-8.59(m, 1H), 8.30-8.29 (m, 1H), 8.15-8.11 (m, 1H), 8.00-7.96 (m, 2H),7.71-7.63 (m, 1H), 7.56-7.52 (m, 2H), 7.47-7.41 (m, 1H), 7.16-7.09 (m,1H), 4.99-4.84 (m, 1H), 4.80-4.70 (m, 1H), 2.71 (s, 3H), 1.54 (d, 7 Hz,3H).

[0127] Compound AT: ¹H NMR (300 MHz, CDCl₃) 8.51 (br s 1H), 8.39 (d, 8Hz, 2H), 7.99 (d, 8 Hz, 2H), 7.86-7.83 (m, 1H), 7.61-7.50 (m, 1H), 7.49(d, 8 Hz), 7.05-6.99 (m, 1H), 4.70-4.50 (m, 2H), 2.83 (s, 3H), 2.57 (s,3H), 1.50 (d, 7 Hz, 3H).

[0128] Compound BA: ¹H NMR (300 MHz, CDCl₃) 1.54 (d, J=6.9 Hz 3H), 2.7(s, 3H), 4.72 (q, J=5.5 Hz 1H), 5.05 (br. d, J=5 Hz,1H, NH), 7.1-8.55(m, 11H).

[0129] Compound BD : ¹H NMR (300 MHz, CDCl₃) 8.51 (d, 9 Hz, 1H),8.47-8.45 (m, 1H), 8.01-7.97 (m, 2H), 7.71-7.63 (m, 2H), 7.52-7.41 (m,3H), 7.17-7.10 (m, 1H), 5.51 (d, 8 Hz, 1H), 4.90-4.80 (m, 1H), 1.64 (d,7 Hz, 3H).

[0130] Compound BZ: ¹H NMR (300 MHz, CDCl₃) 8.43 (br s, 1H), 8.32 (d, 8Hz, 1H), 8.28-8.22 (m, 1H), 7.94 (d, 8 Hz, 2H), 7.68-7.58 (m, 2H),7.47-7.37 (m, 3H), 7.12-7.06 (m, 1H), 5.72 (d, 8 Hz, 1H), 4.86-4.70 (m,1H), 2.59 (s, 3H), 1.60 (d, 7 Hz, 3H).

[0131] Compound CD: ¹H NMR (300 MHz, CDCl₃): 8.82-8.78 (m, 1H), 8.23 (d,7 Hz, 2H), 8.21-8.07 (m, 1H), 7.81-7.77 (m, 2H), 7.63-7.57 (m, 1H), 7.55(d, 7 Hz, 2H), 7.40-7.32 (m, 1H), 7.20-7.16 (m, 1H), 4.8-4.7 (m, 2H),2.67 (s, 3H), 1.55 (d, 7 Hz, 2H).

[0132] Compound FS: ¹H NMR (300 MHz, CDCl₃) 8.66-8.62 (m, 1H), 8.51-8.47(m, 1H), 8.29-8.24 (m, 1H), 7.99-7.95 (m, 2H), 7.93-7.89 (m, 2H),7.67-7.53 (m, 1H), 7.50-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.13-7.07 (m,1H), 4.78-4.73 (m, 1H), 4.61-4.59 (m, 1H), 2.70 (s, 3H), 1.56 (d, 7 Hz,3H).

[0133] Compound FY: ¹H NMR (300 MHz, CDCl₃) 8.66-8.63 (m, 1H), 8.49-8.46(m, 1H), 8.28-8.25 (m, 1H), 8.01 (d, 8 Hz, 2H), 7.93-7.89 (m, 2H),7.65-7.58 (m, 1H), 7.56 (d, 8 Hz, 2H), 7.47-7.41 (m, 1H), 7.13-7.07 (m,1H), 5.18 (d, 6 Hz, 1H), 4.90-4.80 (m, 1H), 1.66 (d, 7 Hz, 3H).

[0134] Compound GG: ¹H NMR (300 MHz, CDCl₃): 8.88 (d, 1.2 Hz, 1H),8.51-8.56 (m, 2H), 8.31 (dd, 8 Hz, 1 Hz, 1H), 8.18 (dd, 8 Hz, 1 Hz, 1H),8.08-7.96 (m, 3H), 7.62-7.48 (m, 3H), 5.51 (d, 9 Hz, 1H), 4.90-4.70 (m,1H), 1.62 (d, 7 Hz, 3H).

[0135] Compound GH: ¹H NMR (300 MHz, CDCl₃): 8.63 (d, 2 Hz), 8.58-8.55(m, 1H), 8.34-8.28 (m, 2H), 8.07-7.98 (m, 3H), 8.35 (dd, 8 Hz, 2 Hz,1H), 7.55-7.46 (m, 3H), 5.34 (d, 8 Hz, 1H), 4.9-4.8 (m, 1H), 1.64 (d, 6Hz, 3H). Compound GQ/XXIX: ¹H NMR (300 MHz, CDCl₃): δ8.56-8.52 (m, 1H),8.32-8.21 (m, 3H), 8.02-7.92 (m, 4H), 5.42 (d, 9 Hz, 1H), 8.02-7.92 (m,4H), 5.42 (d, 1H, 9 Hz), 4.84-4.78 (m, 1H), 2.16-2.06 (m, 1H), 1.60 (d,7 Hz, 3H), 1.20-1.17 (m, 2H), 0.97-0.89 (m, 1H).

[0136] Compound GR/XXX: ¹H NMR (300 MHz, CDCl₃): δ8.33-8.22 (m, 3H),8.00-7.94 (m, 2H), 7.66-7.58 (m, 1H), 7.53-7.37 (m, 4H), 7.16-7.05 (m,1H), 5.160 (d, 9 Hz, 1H), 4.88-4.83 (m, 1H), 2.17-2.06 (m, 1H), 1.65 (d,7 Hz, 3H), 1.28-1.20 (m, 2H), 0.97-0.90 (m, 2H).

[0137] Compound GS/XXXI: ¹H NMR (300 MHz, CDCl₃): δ8.38-8.29 (m, 2H),8.17 (d, 8 Hz, 1H), 8.07-8.02 (m, 1H), 7.91-7.85 (m, 2H), 7.56-7.36 (m,5H), 6.11 (d, 8 Hz, 1H), 4.84-4.78 (m, 1H), 2.12-2.01 (m, 1H), 1.57 (d,7 Hz, 3H), 1.21-1.12 (m, 2H), 0.92-0.86 (m, 2H).

[0138] Compound GW/XXXVI: ¹H NMR (300 MHz, CDCl₃): δ10.19 (d, 7.8 Hz,1H), 8.27-8.42 (m, 4H), 8.13 (dd, 7.8 Hz, 2.1 Hz, 1H), 7.93 (d, 8.4 Hz,2H), 7.78-7.63 (m, 2H), 7.59 (d, 8.4 Hz, 2H), 4.80 (m, 1H), 1.44 (d, 6.9Hz, 3H).

[0139] Compound HO/XXXXXV: ¹H NMR (300 MHz, CDCl₃): δ8.56 (d, 3.9 Hz,1H), 8.31-8.22 (m, 2H), 8.124 (d, 2.7 Hz, 1H), 8.05-7.95 (m, 1H), 7.92(d, 8.4 Hz, 2H), 7.50-7.45 (m, 1H), 7.92 (d, 8.4 Hz, 2H), 7.27-7.23 (m,2H), 5.8 (d, NH, 1H), 4.85-4.75 (m, 1H), 3.99 (s, 3H), 1.58 (d, 7.2 Hz,3H).

[0140] Compound HP/XXXXXVI: ¹H NMR (300 MHz, CDCl₃): δ8.56-8.52 (m, 1H),8.31-8.23 (m, 3H), 8.02-7.90 (M, 4H), 4.87-4.78 (d, 7 Hz, 1H), 4.69 (m,1 H), 2.66 (s, 3H), 2.16-2.06 (m, 1H), 1.51 (d, 7 Hz, 3H), 1.27-1.17 (m,2H), 0.96-0.90 (m, 2H).

[0141] The compounds of the present invention exhibit anti-inflammatoryand/or immunomodulatory activity and are useful in the treatment ofvarious medical conditions including, e.g., rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes,osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia,nephritis, psoriasis, allergy, inflammatory disorders of the lungs andgastrointestinal tract such as Crohn's disease, and respiratory tractdisorders such as reversible airway obstruction, asthma, chronicobstructive pulmonary disease (COPD) and bronchitis. This utility ismanifested as demonstrated by activity in the following assay.

[0142] Potential cannabinoid receptor ligands were screened for theability to compete with [³H] CP-55,940 for binding to recombinantcannabinoid receptors. Test compounds were serially diluted in DiluentBuffer (50 mM Tris pH 7.1, 1 mM EDTA, 3 mM MgCl₂, 0.1% BSA, 10% DMSO,0.36% methyl cellulose (Sigma M-6385)) from stocks prepared in 100%DMSO. Aliquots (10 ul) were transferred into 96-well microtiter plates.Membrane preparations of recombinant human cannabinoid CB2 receptor(Receptor Biology #RB-HCB2) or recombinant human cannabinoid CB1receptor (Receptor Biology #RB-HCB1) were diluted to 0.3 mg/ml inBinding Buffer (50 mM Tris pH 7.2, 1 mM EDTA, 3 mM MgCl₂, 0.1% BSA).Aliquots (50 ul) were added to each well of the microtiter plate. Thebinding reactions were initiated by addition of [³H] CP-55,940 (NewEngland Nuclear # NET 1051; specific activity=180 Ci/mmol) to each wellof the microtiter plate. Each 100 ul reaction mixture contained 0.48 nM[³H] CP-55,940, 15 ug membrane protein in binding buffer containing 1%DMSO and 0.036% methyl cellulose. Following incubation for 2 hours atroom temperature, the reactions were filtered through 0.5%polyethylenimine-coated GF/C filter plates (UniFilter-96, Packard) witha TomTec Mark 3U Harvester (Hamden, Conn.). The filter plate was washed5 times with binding buffer, rotated 1800, then re-washed 5 times withbinding buffer. Bound radioactivity was quantitated following additionof 30 ul of Packard Microscint 20 scintillant in a Packard TopCount NXTmicroplate scintillation counter. Non-linear regression analysis of theresulting data was performed using Prism 2.0b (GraphPad, San Diego,Calif.).

[0143] Cannabinoid receptor ligands according to the present inventionhave anti-inflammatory activity and/or immunomodulatory activity and areuseful in the treatment of various medical conditions including, e.g.,cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupuserythematosus, multiple sclerosis, glaucoma, diabetes, osteoporosis,renal ischemia, myocardial infarction, cerebral stroke, cerebralischemia, nephritis, hepatitis, glomerulonephritis, cryptogenicfibrosing aveolitis, psoriasis, atopic dermatitis, vasculitis, allergy,seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease,reversible airway obstruction, adult respiratory distress syndrome,asthma, chronic obstructive pulmonary disease (COPD) or bronchitis. Itis contemplated that a compound of this invention may be useful intreating more than one of the diseases listed.

[0144] Additionally, a compound of the present invention may beco-administered or used in combination with disease-modifyingantirheumatic drugs (DMARDS) such as methotrexate, azathioptrineleflunomide, pencillinamine, gold salts, mycophenolate mofetil,cyclophosphamide and other similar drugs. They may also beco-administered with or used in combination with NSAIDS such aspiroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2selective inhibitors such as Vioxx® and Celebrex®; COX-1 inhibitors suchas Feldene; immunosuppressives such as steroids, cyclosporine,Tacrolimus, rapamycin and the like; biological response modifiers (BRMs)such as Enbrel, Remicade, IL-1 antagonists, anti-CD40, anti-CD28, IL-10,anti-adhesion molecules and the like; and other anti-inflammatory agentssuch as p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors,chemokine receptor antagonists, Thalidomide and other small moleculeinhibitors of pro-inflammatory cytokine production. Other drugs that thecompounds of the invention may be co-administered or used in combinationwith include Anaprox, Arava, Arthrotec, Azulfidine, Aspirin, Cataflam,Celestone Soluspan, Clinoril, Cortone Acetate, Cuprimine, Daypro,Decadron, Depen, Depo-Medrol, Disalcid, Dolobid, Naprosyn, Gengraf,Hydrocortone, Imuran, Indocin, Lodine, Motrin, Myochrysine, Nalfon,Naprelan, Neoral, Orudis, Oruvail, Pediapred, Plaquenil, Prelone,Relafen, Solu-Medrol, Tolectin, Trilisate and Volataren. These includeany formulation of the abovenamed drugs.

[0145] For the treatment of multiple sclerosis, the compounds of theinvention may be co-administered or used in combination with Avonex,Betaseron and Copaxone.

[0146] For combination treatment with more than one active agent, wherethe active agents are in separate dosage formulations, the active agentsmay be administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

[0147] The present invention also relates to a pharmaceuticalcomposition comprising a compound of formula I of this invention and apharmaceutically acceptable carrier. The compounds of formula I can beadministered in any conventional dosage form known to those skilled inthe art. Pharmaceutical compositions containing the compounds of formulaI can be prepared using conventional pharmaceutically acceptableexcipients and additives and conventional techniques. Suchpharmaceutically acceptable excipients and additives include non-toxiccompatible fillers, binders, disintegrants, buffers, preservatives,anti-oxidants, lubricants, flavorings, thickeners, coloring agents,emulsifiers and the like. All routes of administration are contemplatedincluding, but not limited to, parenteral, transdermal, subcutaneous,intramuscular, sublingual, inhalation, rectal and topical.

[0148] Thus, appropriate unit forms of administration include oral formssuch as tablets, capsules, powders, cachets, granules and solutions orsuspensions, sublingual and buccal forms of administration, aerosols,implants, subcutaneous, intramuscular, intravenous, intranasal,intraoccular or rectal forms of administration.

[0149] When a solid composition is prepared in the form of tablets,e.g., a wetting agent such as sodium lauryl sulfate can be added tomicronized or non-micronized compounds of formula I and mixed with apharmaceutical vehicle such as silica, gelatin starch, lactose,magnesium stearate, talc, gum arabic or the like. The tablets can becoated with sucrose, various polymers, or other appropriate substances.Tablets can be treated so as to have a prolonged or delayed activity andso as to release a predetermined amount of active principle continuouslyor at predetermined intervals, e.g., by using ionic resins and the like.

[0150] A preparation in the form of gelatin capsules may be obtained,e.g., by mixing the active principle with a diluent, such as a glycol ora glycerol ester, and incorporating the resulting mixture into soft orhard gelatin capsules.

[0151] A preparation in the form of a syrup or elixir can contain theactive principle together, e.g., with a sweetener, methylparaben andpropylparaben as antiseptics, flavoring agents and an appropriate color.

[0152] Water-dispersible powders or granules can contain the activeprinciple mixed, e.g., with dispersants, wetting agents or suspendingagents, such as polyvinylpyrrolidone, as well as with sweeteners and/orother flavoring agents.

[0153] Rectal administration may be provided by using suppositorieswhich may be prepared, e.g., with binders melting at the rectaltemperature, for example cocoa butter or polyethylene glycols.

[0154] Parenteral, intranasal or intraocular administration may beprovided by using, e.g., aqueous suspensions, isotonic saline solutionsor sterile and injectable solutions containing pharmacologicallycompatible dispersants and/or solubilizers, for example, propyleneglycol or polyethylene glycol.

[0155] Thus, to prepare an aqueous solution for intravenous injection,it is possible to use a co-solvent, e.g., an alcohol such as ethanol ora glycol such as polyethylene glycol or propylene glycol, and ahydrophilic surfactant such as Tween® 80. An oily solution injectableintramuscularly can be prepared, e.g., by solubilizing the activeprinciple with a triglyceride or a glycerol ester.

[0156] Topical administration can be provided by using, e.g., creams,ointments or gels.

[0157] Transdermal administration can be provided by using patches inthe form of a multilaminate, or with a reservoir, containing the activeprinciple and an appropriate solvent.

[0158] Administration by inhalation can be provided by using, e.g., anaerosol containing sorbitan trioleate or oleic acid, for example,together with trichlorofluoromethane, dichlorofluoromethane,dichlorotetrafluoroethane or any other biologically compatiblepropellant gas; it is also possible to use a system containing theactive principle, by itself or associated with an excipient, in powderform.

[0159] The active principle can also be formulated as microcapsules ormicrospheres, e.g., liposomes, optionally with one or more carriers oradditives.

[0160] Implants are among the prolonged release forms which can be usedin the case of chronic treatments. They can be prepared in the form ofan oily suspension or in the form of a suspension of microspheres in anisotonic medium.

[0161] The daily dose of a compound of formula I for treatment of adisease or condition cited above is about 0.001 to about 100 mg/kg ofbody weight per day, preferably about 0.001 to about 10 mg/kg. For anaverage body weight of 70 kg, the dosage level is therefore from about0.1 to about 700 mg of drug per day, given in a single dose or 2-4divided doses. The exact dose, however, is determined by the attendingclinician and is dependent on the potency of the compound administered,the age, weight, condition and response of the patient.

EXAMPLE I

[0162]

[0163] Compound 1. TFAA (67 mL, 0.474 mol) was dissolved in CH₂Cl₂ (300mL) and cooled in an ice water bath. A solution of(S)-α-methylbenzylamine (56.4 g, 0.465 mol) dissolved in CH₂Cl₂ (100 mL)was added and the ice bath was removed. The reaction mixture was stirredat rt for 3 h. The reaction mixture was cooled in an ice bath and MsOH(80 mL, 1.23 mol) was added followed by DBDMH (65 g, 0.227 mol). Thereaction mixture was left stirring overnight at rt then quenched with 1Maq NaHSO₃. The organic layer was washed with water and brine, dried withMgSO₄, and concentrated to give 130 g of white solid. The crude productwas recrystallized from Et₂O and hexanes giving 46 g (32%) ofintermediate Compound 1 as a solid.

[0164] Compound 2. In a flame dried flask under N₂ blanket, Compound 1(12.35 g, 41.2 mmol) was dissolved in dry THF (165 mL) and cooled to−78° C. Methyllithium (1.4 M in Et₂O, 30 mL, 42 mmol) was added and thereaction mixture was stirred for 5 min. n-BuLi (1.6 M in hexanes, 26 mL,42 mmol) was added followed after 10 min by p-methoxybenzenesulfonylfluoride (8.64 g, 45.4 mmol) which was prepared by standard methods. Thecold bath was removed after 10 min and the reaction mixture was allowedto warm to rt over 45 min then quenched with pH 7 sodium phosphatebuffer (1 M, 100 mL, 100 mmol). The reaction mixture was extracted withEtOAc and the resulting organic layer was washed with brine and driedwith MgSO₄. After evaporation of the solvent, the crude product waspurified by sgc (20%-50% EtOAc/hexanes gradient) to give 10.39 g (65%)of Compound 2 as a solid.

[0165] Compound 3. In a flame dried flask under N₂ blanket, Compound 2(11.09 g, 28.6 mmol) was dissolved in anhyd THF (100 mL) and cooled to−78° C. A solution of n-BuLi (2.5 M in hexanes, 24 mL, 60 mmol) wasadded and the reaction mixture was stirred for 40 min.Bis-4-methoxyphenyl disulfide (8.76 g/31.5 mmol) was added and thereaction mixture was stirred at −78° C. for 40 min then between −15° C.and −30° C. for 5 h then quenched with pH 7.0 sodium phosphate buffer(1.0 M, 120 mL). The reaction mixture was partitioned between EtOAc andwater. The aqueous layer was extracted with additional EtOAc. Thecombined organic layer was washed with aq Na₂CO₃ and brine, then driedwith MgSO₄ and concentrated to dryness. The crude product (13.8 g yellowfoam) was dissolved in CH₂Cl₂ (120 mL) and cooled to 0° C. MCPBA (18.5g, ca 107 mmol) was added, followed by additional CH₂Cl₂ (40 mL). Theice bath was removed and the reaction mixture was stirred at rt forovernight. Aqueous NaHCO₃ (200 mL) and CH₂Cl₂ were added and the layerswere separated. The organic layer was washed with aq NaHSO₃, NaHCO₃,H₂O, and brine then dried with MgSO₄. The crude product was purified bysgc (30% to 50% EtOAc/hexanes gradient) to give 7.21 g (45%) of Compound3.

[0166] Compound 4. Compound 3 (4.47 g, 8.02 mmol) was dissolved inp-dioxane (16 mL) and cooled to 0° C. LiOH (1.0 M aq, 10 mL, 10 mmol)was added and the ice bath was removed. The reaction mixture was stirredat rt for 6 h then concentrated. CH₂Cl₂ (100 mL) and NaOH (1.0 M aq, 10mL) were added and the layers were separated. The aqueous layer wasextracted with additional CH₂Cl₂ and the combined organic layer wasdried with MgSO₄ and concentrated. The crude product was purified by sgc(2%-10% MeOH (NH₃)/CH₂Cl₂ gradient mobile phase) to give 3.23 g (87%) ofCompound 4.

[0167] Compound I. Compound 4 (3.08 g, 6.67 mmol) was dissolved inCH₂Cl₂ (33 mL) and triethylamine (1.40 mL, 10.0 mmol) then cooled to 0°C. MsCl (569 μL, 7.34 mmol) was added and the reaction mixture wasstirred at 0° C. for 1 h and 15 min. Citric acid (0.5 M, 40 mL) andadditional CH₂Cl₂ were added and the layers were separated. The organiclayer was washed with citric acid, NaHCO₃, and brine then dried withMgSO₄. The solvent was evaporated and the crude product was purified bysgc (40%-70% EtOAc/hexanes gradient) to give 3.44 g (96%) of Compound 1as a solid.

[0168] Compound II. Compound 4 (27.5 mg, 0.0595 mmol) was dissolved inmethylene chloride (226 μL) and DIPEA (12 μL). A solution of propionylchloride dissolved in 1,2-dichloroethane (1 M, 75 μL, 0.075 mmol) wasadded and the reaction mixture was shaken at room temperature overnight.Tris(2-aminoethyl)amine polystyrene (4.1 mmol N/g, ca 60 mg) was addedto the reaction mixture. The reaction mixture was shaken for anadditional hour at rt. The crude product was concentrated, thendissolved in EtOAc and filtered through a silica-gel SepPak (WatersCorp.). The resulting filtrate was concentrated to give 9 mg (29%) ofCompound II.

[0169] Compound III. Compound 4 (25 mg, 0.054 mmol) was dissolved inCH₂Cl₂ (270 μL). A solution of phenyl isocyanate dissolved in toluene(1.0 M, 65 mL, 0.065 mmol) was added and the reaction mixture was shakenat rt overnight. Tris(2-aminoethyl)amine polystyrene (4.1 mmol N/g, ca60 mg) was added to the reaction mixture and the reaction mixture wasshaken for an additional 40 min at rt. EtOAc was added and the reactionmixture was filtered through a silica gel SepPak (Waters Corp.). Theresulting filtrate was concentrated to give 18 mg (57%) of Compound III.

EXAMPLE II

[0170]

[0171] Compound 5. In a 3-necked flame-dried flask under N₂ blanketCompound 1 (40.0 g, 134 mmol) was dissolved in anhyd THF (535 mL) andcooled to −75° C. (internal temperature). A solution of methyllithium(1.4 M in diethyl ether, 105 mL, 147 mmol) was added at a rate that keptthe internal temperature below −60° C. The reaction was stirred for 15min and a solution of n-BuLi (2.5 M in hexanes, 62 mL, 155 mmol) wasadded at a rate that maintained the internal temperature of the reactionbelow −65° C. The reaction mixture was stirred for 40 min. and asolution of bis(4-chlorophenyl)disulfide (42 g, 146 mmol) dissolved inanhyd THF (90 mL) was added via addition funnel over 1 h. The reactionmixture was stirred for 3 h then quenched with HCl (1 M aqueous, 200 mL,200 mmol). EtOAc (500 mL) was added and the layers were separated. Theaqueous layer was extracted with 500 mL EtOAc, and the combined organiclayer was washed with 1 M aq KOH, water, and brine. After drying withMgSO₄, the solvent was evaporated to give 54.1 g of a solid. The crudeproduct (52.3 g) was dissolved in CH₂Cl₂ (750 mL) and cooled to 2° C.(internal temp). MCPBA (60%, 184 g) was added in portions over 1 hr and20 min keeping the internal temperature below 15° C. The reactionmixture was stirred an additional 2 h. NaOH (1 M aq, 500 mL) and CH₂Cl₂were added and the layers were separated. The aqueous layer wasextracted with an additional 300 mL of CH₂Cl₂. The combined organiclayer was washed with 1M aqueous NaOH, water, and brine, then dried withMgSO₄. After evaporation of the solvent, a solid (65 g) was obtained.The crude product was partially purified by trituration fromEt₂O/hexanes to give 33.3 g of a solid which was subsequently purifiedvia sgc (20%-25% EtOAc/hexanes) to give 30 g (57%) of Compound 5 as asolid.

[0172] Compound 6. In a flame dried 3-necked flask under N₂ blanketCompound 5 (44 g, 112 mmol) was dissolved in anhyd THF (450 mL) andcooled in a dry ice/IPA bath. A solution of n-butyl lithium (2.5 M inhexanes, 92 mL, 230 mmol) was added at a rate that maintained theinternal reaction temperature below −60° C., and the reaction mixturewas stirred for 1 h. A solution of 2-fluorobenzenesulfonyl fluoride(22.3 g, 125 mmol) dissolved in anhyd THF (20 mL) was added and thereaction mixture was left stirring overnight and allowed to warm to rt.The reaction mixture was cooled to 0° C. and quenched with saturated aqammonium chloride (300 mL). EtOAc (600 mL) and brine (25 mL) were addedand the layers were separated. The organic layer was washed with waterand brine, then dried with MgSO₄. The solvents were evaporated giving afoam (62 g). The product was purified by sgc (20%-25% EtOAc/hexanesmobile phase) giving 9.1 g (15%) of Compound 6.

[0173] Compound 7. Compound 6 (6.77 g, 12.3 mmol) was dissolved indioxane (15 mL) and cooled in an ice bath. Aqueous lithium hydroxide (1M, 15 mL, 15 mmol) was added and the reaction mixture was left stirringovernight. The reaction mixture was concentrated, then partitionedbetween CH₂Cl₂ and water. The aqueous layer was extracted withadditional CH₂Cl₂ and the combined organic layer was dried with MgSO₄.Evaporation of the solvent afforded 5.66 g of a foam which was purifiedby sgc (10% MeOH (NH₃)/CH₂Cl₂) to give 4.27 g of Compound 7 (77%).

[0174] Compound IV. Compound 7 (2.66 g, 5.86 mmol) was dissolved inCH₂Cl₂ (28 mL) and triethylamine (0.98 mL) and cooled to 0° C. MsCl(0.499 mL, 6.45 mmol) was added and the reaction mixture was stirred at0° C. for 6 h. The reaction mixture was partitioned between water andCH₂Cl₂. The aqueous layer was extracted with additional CH₂Cl₂ and thecombined organic layer was dried with MgSO₄. Evaporation of the solventafforded 3.0 g of a foam which was purified by sgc (40%-50%EtOAc/hexanes gradient) to give 2.77 g (89%) of Compound IV.

[0175] Compound IV: ¹H NMR (300 MHz, CDCl₃) 8.61-5.97 (m, 2H), 8.40 (d,8 Hz, 1H), 8.24-8.21 (m, 1H), 7.96 (d, 8 Hz, 2H), 7.86-7.83 (m, 1H),7.70-7.63 (m, 1H), 7.52 (d, 8 Hz, 2H), 7.46-7.40 (m, 1H), 7.18-7.12 (m,1H), 4.80-4.70 (m, 1H), 2.71 (s, 3H), 1.56 (d, 7 Hz, 3H).

[0176] Compound V. Compound 7 (26.1 g, 57.4 mmol) was dissolved inCH₂Cl₂ (200 mL) and triethylamine (20 mL) and cooled to −78° C. Triflicanhydride (10.45 mL, 62.1 mmol) was added and the reaction mixture wasstirred for 3 h. The reaction was quenched with water and the layerswere separated. The organic layer was washed with water and brine, thendried with MgSO₄. The solvent was evaporated to give 42 g of a foam. Thecrude product was purified via sgc (33%-50% EtOAc/hexanes gradient) togive 29.7 g (88%) of Compound V.

[0177] Compound V: ¹ H NMR (300 MHz, CDCl₃) 8.61-8.59 (m,1H), 8.39 (d, 8Hz, 1H), 8.29-8.24 (m, 1H), 7.99 (d, 8 Hz, 2H), 7.86-7.82 (m, 1H),7.67-7.62 (m, 1H), 7.49 (d, 8 Hz, 1H), 7.46-7.40 (m, 1H), 7.16-7.10 (m,1H), 4.89-4.84 (m, 1H), 1.65 (d, 6 Hz, 1H).

[0178] Compound VI. Compound V (300 mg, 0.512 mmol) was dissolved inmethanol (60 mL). Sodium bicarbonate (720 mg, 8.57 mmol) and 5%palladium on carbon (480 mg) were added. The reaction mixture was shakenon a Parr apparatus under 52 psi of hydrogen gas overnight. The reactionmixture was filtered and the solvent was evaporated. The resultingmaterial was partitioned between EtOAc and aq NaHCO₃. The organic layerwas dried with MgSO₄ and the solvents were evaporated. The crude productwas purified via sgc (33% EtOAc/hexanes) to give 257 mg (91%) ofCompound VI.

EXAMPLE III

[0179]

[0180] Compound 8. In a flame dried 3-necked flask under N₂ blanketCompound 5 (35.7 g, 91 mmol) was dissolved in anhyd THF (360 mL) andcooled in a dry ice/IPA bath. A solution of n-BuLi (2.5 M in hexanes, 76mL, 190 mmol) was added at a rate that maintained the internaltemperature below −60° C. The reaction mixture was stirred for 1 h. Asolution of 2,6-difluorobenzenesulfonyl fluoride (19.47 g, 99.28 mmol)dissolved in anhyd THF (60 mL) was added. The reaction mixture wasstirred for 2.5 h, then quenched with saturated aq NH₄Cl (400 mL). EtOAc(500 mL) was added and the layers were separated. The aq layer wasextracted with EtOAc and the combined organic layer was washed withbrine and dried with MgSO₄. The solvent was evaporated to give 60.7 g ofan oil which was purified by sgc (15%-40% EtOAc/hexanes gradient) giving14.4 g (28%) of Compound 8.

[0181] Compound 9. Compound 8 (21.1 g, 37.2 mmol) was dissolved indioxane (47 mL) and aq lithium hydroxide (1.0 M, 41 mL, 41 mmol) wasadded. After 5.5 h, additional LiOH (20 mL) was added and the reactionmixture was stirred overnight. The reaction mixture was extracted withCH₂Cl₂, and partitioned between CH₂Cl₂ and water. The aq layer wasextracted with additional CH₂Cl₂ and the combined organic layer wasdried with MgSO₄. The solvents were evaporated to give 17.6 g of a foamand the crude product was purified by sgc (1%-3% MeOH (NH₃)/CH₂Cl₂gradient) to give 12.2 g (69%) of Compound 9.

[0182] Compound VII. Compound 9 (10.7 g, 22.6 mmol) was dissolved in amixture of CH₂Cl₂ (90 mL) and triethylamine (8mL) and cooled to −78° C.Triflic anhydride (3.80 mL, 22.6 mmol) was added and the reactionmixture was stirred for 2 h. The reaction was quenched with saturated aqNaHCO₃ and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂. The combined organic layer was washed with brine and driedwith MgSO₄. The solvents were evaporated and the crude product waspurified by sgc to give 9.88 g (73%) of Compound VII.

EXAMPLE IV

[0183] Compound 5. In a flame dried flask under N₂ blanket Compound 1(39.2 g, 132 mmol) was dissolved in anhyd THF (1 L) and cooled in a dryice/acetone bath. A solution of methyllithium (1.6 M in Et₂O, 82.7 mL,132 mmol) was added followed by a solution of n-BuLi (2.5 M in hexanes,53 mL, 133 mmol). The reaction mixture was stirred for 25 min and asolution of bis(4-trifluoromethylphenyl)disulfide (46.9 g, 132 mmol)dissolved in THF (200 mL) was added. The reaction mixture was stirredfor 2 h then allowed to warm to rt overnight. The reaction was quenchedwith water and concentrated. The resulting mixture was diluted withEtOAc, washed with water, and dried with Na₂SO₄. The solvent wasevaporated and the crude product was purified via sgc (20%EtOAc/hexanes) to give 49.2 g (95%) of a solid. This material (49.2 g)was dissolved in CH₂Cl₂ (1.2 L) and cooled in an ice bath. MCPBA (60%,90 g) was added in small portions. After 1 h, the ice bath was removedand the reaction mixture was stirred overnight at rt. The reactionmixture was partitioned between CH₂Cl₂ and 10% aqueous NaHCO₃. Thecombined organic layer was washed with water and dried with Na₂SO₄. Thesolvent was evaporated and the crude product was purified by sgc (25%EtOAc/hexanes) to give 46.3 g (85%) of Compound 5.

[0184] Compound 10. In a flame dried flask under N₂ blanket, Compound 5(21.55 g, 50.7 mmol) was dissolved in anhyd THF (300 mL) and cooled in adry ice/IPA bath. A solution of methyllithium (1.6 M in Et₂O, 32 mL, 51mmol) was added, followed by n-BuLi (2.5 M in hexanes, 20.3 mL, 50.7mmol) and the reaction mixture was stirred for 10 min. A solution ofbis-(2-fluorophenyl)disulfide (14.2 9, 55.7 mmol) dissolved in THF wasadded and the reaction mixture was stirred for 2 h at −78° C. The icebath was removed and the reaction mixture was allowed to warm to rt andleft stirring overnight. The reaction mixture was quenched withsaturated aqueous NH₄Cl and extracted with EtOAc. The organic layer wasdried with Na₂SO₄ and the solvents were evaporated. The crude productwas purified via sgc (25% EtOAc/hexanes) to give 23.2 g of a solid. Thismaterial was dissolved in CH₂Cl₂ (400 mL) and cooled in an ice bath.MCPBA (60%, 30.3 g) was added in several portions and the reactionmixture was stirred for 1 h. The ice bath was removed and the reactionmixture was left stirring overnight. The reaction mixture waspartitioned between CH₂Cl₂ and 5% aq Na₂CO₃. The organic layer waswashed with water and dried with Na₂SO₄. The solvents were evaporatedand the crude product was purified via sgc (25% EtOAc/hexanes) to give10.84 9 (44%) of Compound 10.

[0185] Compound 11. Compound 10 (11.88 g, 20.36 mmol) was dissolved indioxane (200 mL) and aq lithium hydroxide (1.0 M, 400 mL) was added. Thereaction mixture was stirred for 3 h then and partitioned between CH₂Cl₂and water. The organic layer was dried with Na₂SO₄ and concentrated togive 9.34 g (99%) of Compound 11.

[0186] Compound VIII. Compound 11 (0.63 g, 1.29 mmol) was dissolved in amixture of CH₂Cl₂ (60 mL) and triethylamine (0.27 mL) and cooled in anice bath. Triflic anhydride (0.55 g, 1.95 mmol) was added and thereaction mixture was stirred for 1 h. The ice bath was removed, and thereaction mixture was stirred an additional 3 h. The reaction waspartitioned between water and CH₂Cl₂. The organic layer was washed withwater and dried with Na₂SO₄. The solvent was evaporated and the crudeproduct was purified by sgc (20% EtOAc/hexanes) to give 0.53 g (66%) ofCompound VIII.

[0187] Compound VIII: ¹H NMR (300 MHz, CDCl₃) 8.89-8.87 (m, 1H), 8.58(d, 8 Hz, 1H), 8.32-8.25 (m, 1H), 8.15-8.11 (m, 1H), 8.03-7.98 (m, 2H),7.71-7.63 (m,1H), 7.52-7.48 (m, 2H), 7.47-7.41 (m, 1H), 7.16-7.09 (m,1H), 5.62 (d, 8 Hz, 1H), 4.90-4.80 (m, 1H), 1.63 (d, 7 Hz, 3H).

EXAMPLE V

[0188]

[0189] Potassium hydroxide (3.1 g, 55.2 mmol), 2-bromo-4-chlorophenol(9.52 g, 45.9 mmol), and 4-fluorobenzonitrile (5.73 g, 47.3 mmol) wereadded to DMA (25 mL) and the reaction mixture was stirred between 100°C. and 110° C. for one week. The reaction mixture was stirred at rt anadditional two days. The solvents were partially removed on the rotaryevaporator and the resulting mixture was partitioned between water and a3:1 Et₂O/hexanes solution. The organic layer was washed with water andbrine, then dried with MgSO₄. The solvents were evaporated and the crudeproduct was purified by sgc (20%-30% CH₂Cl₂/hexanes) to give 11.96 g(81%) of an oil.

[0190] Compound 12. The product of the above step (5.90 g, 19.1 mmol)was placed under N₂ atmosphere and a solution of borane in THF (1.0 M,21 mL, 21 mmol) was added causing an exotherm. Once the reaction mixturehad returned to rt, it was heated to reflux and stirred at refluxovernight. Additional borane in THF (1.0 M, 20 mL, 20 mmol) was addedand the reaction mixture was stirred at reflux for an additional 26 hthen allowed to cool to rt. Water (55 mL) was added and the reactionmixture was partially concentrated. The resulting mixture waspartitioned between EtOAc and aq NaOH (1.0 M). The organic layer wasdried with MgSO₄ and concentrated to give 6.2 g of an oil. This materialwas dissolved in Et₂O and a solution of HCl in Et₂O was added causingCompound 12 (5.2 g, 78%) to precipitate as a solid.

[0191] Compound 13. Compound 12 (5.13 g, 16.6 mmol) was suspended in amixture of CH₂Cl₂ (40 mL) and triethylamine (7.5 mL). The mixture wascooled in an ice-water bath and TFAA (2.35 mL, 16.6 mmol) was added. Thereaction mixture was stirred for 1 h and 20 min and the ice bath wasremoved. The reaction mixture was stirred for an additional 1 h and 20min at rt. The reaction mixture was diluted with CH₂Cl₂ (100 mL) andwashed with aq citric acid (0.5 M), saturated aq NaHCO₃, water, andbrine, then dried with MgSO₄. The solvents were evaporated and the crudeproduct (5.22 g) was purified via sgc (10%-20% EtOAc/hexanes gradient)to give Compound 13.

[0192] Compound 14. In a flame dried flask under N₂ blanket, Compound 13(1.00 g, 2.47 mmol) was dissolved in anhyd THF (13 mL) and cooled in adry ice/IPA bath. Methyllithium (1.4 M in Et₂O, 2.3 mL, 3.22 mmol) wasadded, followed by n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol). Thereaction mixture was stirred for 1 h at −78° C. A solution of2,6-difluorobenzenesulfonyl fluoride (1.10 g, 5.60 mmol) dissolved inTHF was added and the reaction mixture was stirred for 4 h. The reactionmixture was quenched with pH 7 sodium phosphate buffer (1.0 M) and EtOAcwas added. The layers were separated and the aqueous layer was extractedwith additional EtOAc. The combined organic layer was washed with brineand dried with MgSO₄. The solvents were evaporated and the crude productwas purified via sgc (20%-33% EtOAc/hexanes) gradient to give 76 mg ofCompound 14.

[0193] Compound 15. Compound 14 (59 mg, 0.12 mmol) was dissolved in 700μL of dioxane and LiOH (1.0 M, 300 μL, 0.3 mmol) was added. The reactionmixture was stirred at rt for 24 h then partitioned between CH₂Cl₂ and1.0 M aq NaOH. The organic layer was dried with MgSO₄ and concentrated.The crude product was purified via PTLC (Merck-silica plates, 3%(MeOH/NH₃)/CH₂Cl₂) to give the desired Compound 15. (21 mg, 45%).

[0194] Compound IX. Compound 15 (17 mg, 0.042 mmol) was dissolved inCH₂Cl₂ (166 μL) and DIPEA (20 μL). The flask was cooled in an ice/waterbath and MsCl (12 μL, 0.15 mmol) was added. The reaction mixture wasstirred at 0° C. for 1 h and 30 min. The resulting mixture waspartitioned between water and CH₂Cl₂. The organic layer was washed withwater and brine, then dried with MgSO₄. The crude product was purifiedvia PTLC (50% EtOAc/hexanes) to give 10 mg (50%) Compound IX.

EXAMPLE VI

[0195]

[0196] Compound 16 (0.116 g, 0.22 mmoles) was dissolved in CH₂Cl₂ (4 mL)and cooled to 0° C. BBr₃ solution (1.0 M in CH₂Cl₂, 0.66 mL) was addedand the ice bath was removed. The reaction mixture was stirred at rt for48 h and then quenched with water at −78° C. The reaction mixture wasdiluted with CH₂Cl₂ and the resulting organic layer was washed withaqueous NaHCO₃, H₂O (3×5 mL), and brine. The organics were dried overNa₂SO₄ and the solvent was removed under vacuum to give 0.09 g of crudeproduct. The product was isolated by PTLC (5% CH₃OH/CH₂Cl₂) to provideCompound X (0.01 g, 8.8%).

[0197] Compound 16: ¹H NMR (300 MHz, CDCl₃) 1.54 (d, J=6.9 Hz 3H), 2.67(s, 3H), 4.72 (q, J=5 Hz 1H), 4.86 (br. d, J=5 Hz,1H, NH), 7.08-8.42 (m,11H).

EXAMPLE VII

[0198]

[0199] Compound 17 was converted to Compound 18 using the procedure inexample VI.

[0200] Compound 18 (0.34 g, 0.64 mmoles) was dissolved in DMF (11 mL),cesium carbonate (0.84 g, 2.58 mmol) was added and the reaction mixturewas cooled to 15° C. Dry bromodifluoromethane gas was introduced intothe solution and bubbled for 15-20 min. Progress of the reaction wasmonitored by TLC and upon completion the reaction mixture was dilutedwith EtOAc (20 mL), washed with water (4×10 mL), and brine. The organicswere dried over Na₂SO₄ and concentrated under reduced pressure to give0.36 g of an oil. The crude product was purified by PTLC (50%EtOAc/hexanes) to provide 0.31 g (83%) of Compound 19.

[0201] Compound 19 was converted to Compound XI using the procedure inexample II.

[0202] Compound XI: ¹H NMR (400 MHz, CDCl₃) 1.51 (d, J=7.2 Hz 3H), 2.67(s, 3H), 4.702 (q, J=6.8 Hz 1H), 5.05 (br. d, J=6.4 Hz,1H, NH), 6.71 (t,J=71.6 Hz, CF2H) 7.07-8.47 (m, 11H).

EXAMPLE VIII

[0203]

[0204] Compound 20. To a solution of Compound 2 (5.00 g, 12.9 mmol) inanhyd THF (75 mL) at −78° C. was added n-BuLi (13 mL, 2.5 M in hexanes,32 mmol) dropwise over 10 min. The reaction mixture was stirred for 30min. A solution of di-t-butyl dicarbonate (3.10 g, 14.2 mmol) in anhydTHF (25 mL) was added in one portion via cannula. The reaction wasallowed to proceed for 4 h at −78° C. The reaction mixture was thendiluted with EtOAc (˜250 mL) and washed successively with saturated aqNaHSO₄ (˜100 mL), water (˜100 mL), and brine (˜100 mL). The organiclayer was dried over anhyd MgSO₄, filtered, and concentrated underreduced pressure to yield a solid. Further purification of the solid bysgc (25% EtOAc/hexanes) gave 5.32 g (84%) of Compound 20 as a solid.

[0205] Compound XII. Compound 20 (2.06 g, 4.23 mmol) was dissolved inmethanol (40 mL) and a solution of potassium carbonate (2.92 g, 21.1mmol) in water (10 mL) was added. The reaction was allowed to proceedfor 18 h. The solvent was then removed by evaporation under reducedpressure. The resulting white solid was partitioned between water (˜100mL) and EtOAc (−400 mL). The aqueous layer was extracted further withEtOAc (˜100 mL). The combined organic layers were washed with brine(˜500 mL), then dried over anhyd MgSO₄ and filtered. Evaporation of thesolvent gave 1.22 g (74%) of t-butyl2-[(4-(1(S)-aminoethyl)phenyl]sulfonyl-5-methoxybenzoate, an oil, whichwas used in the next step without further purification. MsCl (242 μL,357 mg, 3.12 mmol) was added dropwise to a solution of crude t-butyl2-[(4-(1(S)-aminoethyl)phenyl]sulfonyl-5-methoxybenzoate (1.22 g, 3.12mmol) and triethylamine (522 μL, 379 mg, 3.75 mmol) in anhyd CH₂Cl₂ (3.0mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, thenallowed to warm to rt, and subsequently stirred for 3 h. The reactionmixture was diluted with CH₂Cl₂ (˜50 mL) and washed successively with 1M HCl (˜50 mL), water (3×˜50 mL) and brine (˜50 mL). The organicsolution was dried over anhyd MgSO₄, filtered, and concentrated to yielda solid. Subsequent purification of the crude product by sgc (25%EtOAc/hexanes) gave 1.41 g (96%) of Compound XII as a solid.

EXAMPLE IX

[0206]

[0207] Compound 21. In a flame dried flask under N₂ blanket, Compound 5(400 mg, 1.0 mmol) was dissolved in dry THF (5 mL) and cooled to −78° C.A solution of n-BuLi (1.0 M in hexanes, 1.9 mL, 1.9 mmol) was added andthe reaction mixture was stirred for 30 min. 2-Fluorobenzaldehyde (200mg, 1.6 mmol) was added and the reaction mixture was stirred at −78° C.for 3 h. The reaction mixture was then quenched with saturated aq NH₄Cl(20 mL). Methylene chloride (30 mL) was added and the layers wereseparated. The organic layer was washed with brine, then dried overNa₂SO₄, and concentrated to dryness. The crude product was purified viasgc (25% EtOAc/hexanes) to give 330 mg (62%) of Compound 21 as a powder.

[0208] Compound 22. Compound 21 (10 mg) was dissolved in CH₂Cl₂ (10 mL).Triethylsilane (40 μL, 0.25 mmol) was added followed by BF₃Et₂O (20 μL,0.16 mmol). The reaction mixture was stirred at rt overnight. Afterremoving the solvent, the crude product was purified via PTLC (25%EtOAc/hexanes) to give 6.0 mg (62%) Compound 22 as an oil.

[0209] Compound XIII. Compound 22 (12 mg) was dissolved in methanol (2mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture wasstirred at rt for 2 h. The solvent was removed, CH₂Cl₂ (15 mL) and brine(15 mL) were added, and the layers were separated. The aqueous layer wasextracted with additional CH₂Cl₂ (15 mL) and the combined organic layerswere dried over Na₂SO₄ and concentrated to dryness. The crude productwas then dissolved in CH₂Cl₂ (10 mL) and cooled to 0 ° C. MsCl (14 μL,0.18 mmol) was added followed by addition of pyridine (30 μL, 0.37mmol). The reaction mixture was slowly warmed to rt and stirredovernight. Brine (15 mL) was added and extracted. The organic layer wasdried over Na₂SO₄ and concentrated to dryness. The crude product waspurified via PTLC (25% EtOAc/hexanes) to give 10 mg (86%) of CompoundXIII as an oil.

EXAMPLE X

[0210]

[0211] Compound 23. Compound 21 (330 mg, 0.64 mmol) was dissolved inCH₂Cl₂ (20 mL) at rt. Celite (450 mg) was added followed by addition ofPCC (450 mg, 2.1 mmol). The mixture was stirred at rt overnight. Thesolid was removed by filtration and the organic layer was washed withaq. NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ andconcentrated to dryness. The crude product was purified via sgc (33%EtOAc/hexanes) to give 310 mg (94%) of Compound 23 as a powder.

[0212] Compound XIV. Compound 23 (15 mg) was dissolved in methanol (2mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture wasstirred at rt for 2 h. The solvent was removed and CH₂Cl₂ (15 mL) andbrine (15 mL) were added and the layers separated. The aq layer wasextracted with additional CH₂Cl₂ (15 mL) and the combined organic layerwas dried over Na₂SO₄ and concentrated to dryness. The crude product wasthen dissolved in CH₂Cl₂ (10 mL) and cooled to 0° C. MsCl (15 μL, 0.19mmol) was added followed by addition of pyridine (30 μL, 0.37 mmol). Thereaction mixture was slowly warmed to rt and stirred overnight. Brine(15 mL) was added and extracted. The organic layer was dried over Na₂SO₄and concentrated to dryness. The crude product was purified via PTLC(33% EtOAc/hexanes) to give 9 mg (62%) of Compound XIV as an oil.

[0213] Compound 24. Oven dried methyltriphenylphosphonium bromide (430mg, 1.2 mmol) and LHDMS (1.0 M in hexanes, 1.8 mL, 1.8 mmol) werestirred in dry THF (5 ml) at 0° C. for 20 min., then warmed to rt andstirred for 10 min. A solution of Compound 23 (300 mg, 0.58 mmol) in THF(1 mL) was added dropwise. The mixture was stirred at rt overnight.EtOAc (20 ml) was added and the organic solution was washed with brine.The organic layer was dried over Na₂SO₄ and concentrated to dryness. Thecrude product was purified via PTLC (25% EtOAc/hexanes) to give 260 mg(87%) of Compound 24 as an oil.

[0214] Compound XV. Compound 24 (200 mg, 0.39 mmol) was dissolved inmethanol (3 mL) at rt. NaOH (1.0 M, 3 mL, 3.0 mmol) was added and themixture was stirred at 50° C. for 2 h. The solvent was removed, CH₂Cl₂(20 mL) and brine (20 mL) were added, and the layers were separated. Theaqueous layer was extracted with additional CH₂Cl₂ (15 mL) and thecombined organic layers were dried over Na₂SO₄ and concentrated todryness. The crude product was then dissolved in CH₂Cl₂ (15 mL) andcooled to 0° C. MsCl (200 μL, 2.5 mmol) was added followed by additionof pyridine (400 μL, 4.9 mmol). The reaction mixture was slowly warmedto rt and stirred overnight. Brine (15 mL) was added and the organiclayer separated, dried over Na₂SO₄ and concentrated to dryness. Thecrude product was purified via PTLC (50% EtOAc/hexanes) to give 160 mg(82%) of Compound XV as an oil.

EXAMPLE XI

[0215]

[0216] Compound 26. Compound 25 (1.3 g, 2.7 mmol) was stirred at rt witha mixture of CH₂Cl₂/TFA (2:1, 30 mL) for 3 h. The reaction mixture wasthen poured into brine (40 mL). The layers were separated. The aq layerwas extracted with CH₂Cl₂ (3×30 mL) and the combined organic layers weredried over Na₂SO₄ and concentrated to dryness. The crude product wasdissolved in CH₂Cl₂ (30 mL). EDCl (0.75 g, 3.9 mmol) andpentafluorophenol (0.73 g, 4.0 mmol) were added and the mixture wasstirred at rt overnight. The reaction mixture was extracted with dilutedaq NaOH and washed with brine. The organic layer was then dried overNa₂SO₄ and concentrated to dryness. The crude product was purified viasgc (33% EtOAc/hexanes) to give 1.15 g (72%) of Compound 26 as a foam.

[0217] Compound XVI. Compound 26 (50 mg) was dissolved in CH₂Cl₂ (2 mL).1-Adamantanamine (21 mg, 0.14 mmol) was added followed by addition ofDIPEA (0.05 mL, 0.29 mmol). The reaction mixture was shaken overnight.The reaction mixture was then subjected to Amberlyst 15 resin (300 mg,loading 4.1 mmol/g), and was again shaken overnight. The resin wasremoved by filtration. The filtrate was subjected to MP carbonate resin(Argonaut Technologies) (100 mg, loading 2.64 mmol/g) for 4 h. The resinwas removed by filtration and the filtrate concentrated to give 33 mg(70%) of Compound XVI as a powder.

EXAMPLE XII

[0218]

[0219] Compound 27. Compound 5 (500 mg, 1.3 mmol) was dissolved in dryTHF (6 mL) at rt. NaH (53 mg, 60%, 1.3 mmol) was added, and the reactionmixture was stirred at rt for 1 h. The reaction mixture was then cooledto −78° C., and n-BuLi (1.0 M in hexanes, 1.5 mL, 1.5 mmol) was addeddropwise under N₂ atmosphere. The reaction was stirred at −78° C. for 40min. A solution of I₂ (390 mg, 1.5 mmol) in THF (2 mL) was addeddropwise. The reaction mixture was stirred at −78° C. for 3 h, thenquenched with saturated aq NH₄Cl (20 mL). EtOAc (30 mL) was added andthe layers were separated. The organic layer was washed with brine, thendried over Na₂SO₄, and concentrated to dryness. The crude product (640mg) was used without further purification. The crude product (60 mg) wasdissolved in toluene (2 mL) and Pd(OAc)₂ (2 mg), P^(t)Bu₃ (1 drop),NaO^(t)Bu (14 mg, 0.15 mmol) and p-Chloroaniline (13 mg, 0.11 mmol) wereadded. The mixture was kept in a sealed tube and heated to 120° C. for20 h. After cooling, methylene chloride (30 mL) and brine (20 mL) wereadded and the layers were separated. The organic layer was washed withbrine, then dried over Na₂SO₄, and concentrated to dryness. The crudeproduct was purified with via PTLC (20% EtOAc/hexanes) to give 18 mg(30%) of Compound 27 as a powder.

[0220] Compound XVII. Compound 27 (12 mg) was dissolved in methanol (2mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture wasstirred at rt for 3 h. The solvent was removed, CH₂Cl₂ (20 mL) and brine(20 mL) were added, and the layers were separated. The aq layer wasextracted with additional CH₂Cl₂ (15 mL) and the combined organic layerswere dried over Na₂SO₄ and concentrated to dryness. The crude productwas then dissolved in CH₂Cl₂ (1 5 mL) and cooled to 0° C. MsCl (15 μL,0.19 mmol) and pyridine (30 μL, 0.37 mmol) were added. The reactionmixture was slowly warmed up to rt and stirred overnight. Brine (15 mL)was added and the reaction mixture was extracted with CH₂Cl₂. Theorganic layer was dried over Na₂SO₄ and concentrated to dryness. Thecrude product was purified via PTLC (33% EtOAc/hexanes) to give 6.0 mg(52%) of Compound XVII as an oil.

[0221] Compound 28. Compound 5 (500 mg, 1.3 mmol) was dissolved in dryTHF (6 mL) at rt. NaH (53 mg, 60%, 1.3 mmol) was added, and the mixturewas stirred at rt for 1 h. The reaction mixture was cooled to −78° C.,and n-BuLi (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise under N₂atmosphere, and the temperature was maintained at −78° C. for 40 min. Asolution of I₂ (390 mg, 1.5 mmol) in THF (2 mL) was added dropwise. Thereaction was stirred at −78° C. for 3 h. The reaction mixture wasquenched with saturated aq NH₄Cl (20 mL). EtOAc (30 mL) was added andthe layers were separated. The organic layer was washed with brine, thendried over Na₂SO₄, and concentrated to dryness. The crude product (640mg) was used without further purification. The crude product (60 mg) wasdissolved in toluene (2 mL) and NaH (5 mg, 60%, 0.12 mmol), CuBr.Me₂S(34 mg, 0.17 mmol) and p-chlorophenol (15 mg, 0.12 mmol) were added. Thereaction mixture was kept in a sealed tube and heated to 120° C.overnight. After cooling, CH₂Cl₂ (30 mL) and brine (20 mL) were addedand the layers were separated. The organic layer was washed with brine,then dried over Na₂SO₄, and concentrated to dryness. The crude productwas purified via PTLC (20% EtOAc/hexanes) to give 19 mg (31%) ofCompound 28 as a powder.

[0222] Compound XVIII. Compound 28 (15 mg, 29 μmol) was dissolved inmethanol (2 mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and themixture was stirred at rt for 2 h. The solvent was removed and CH₂Cl₂(20 mL) and brine (20 mL) was added and the layers were separated. Theaq layer was extracted with additional CH₂Cl₂ (15 mL) and the combinedorganic layer was dried over Na₂SO₄ and concentrated to dryness. Thecrude product was then dissolved in CH₂Cl₂ (15 mL) and cooled to 0° C.MsCl (20 μL, 0.25 mmol) was added followed by addition of pyridine (20μL, 0.25 mmol). The reaction mixture was slowly warmed up to rt andstirred overnight. Brine (15 mL) was added and extracted with CH₂Cl₂.The organic layer was dried over Na₂SO₄ and concentrated to dryness. Thecrude product was purified via PTLC (50% EtOAc/hexanes) to give 7.0 mg(48%) of Compound XVII as an oil.

EXAMPLE XIII

[0223]

[0224] Compound 29. To a solution of N,N,N-Trimethylethylenediamine (1.2mL, 8.6 mmol) in THF (8 mL) at −20° C. was added n-BuLi (1.6 M, 5.4 mL,8.6 mmol) dropwise. After 15 min 4-trifluoromethoxybenzaldehyde (1.5 g,7.8 mmol) in THF (8 mL) was added. The mixture was stirred for 15minutes and additional n-BuLi (1.6M, 14.6 mL, 23 mmol) was added. Thereaction mixture was stirred at −20° C. for 1 h, then placed in thefreezer at −20° C. for 20 h. The mixture was cooled to −40° C., and asolution of bis(2-fluorophenyl)disulfide (4.0 g, 15.7 mmoles) in 30 mLTHF was added. The reaction mixture was stirred at −35° C. for 3 h. Thereaction mixture was poured into 0.5 N HCl and extracted with EtOAc. Theorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrated to an oil. Purification by sgc (3%EtOAc/hexanes) gave 1.55 g (62%) of Compound 29 as a solid..

[0225] Compound 30. Methyllithium (3.25 mL, 5 mmol, 1.4 M ether) wasadded to a solution of Compound 1 (1.22 g, 4 mmol) at −70° C. After 10min n-BuLi (1.6 M in hexanes, 2.83 mL, 5 mmol) was added and stirred for30 min. A solution of Compound 29 (1.44 g, 4.55 mmoles), dissolved inTHF (15 mL) was added. The resulting mixture was stirred at −70° C. for2.5 h, quenched with water, warmed to 0° C. and then extracted with 2×50mL EtOAc. The organic layer was washed with water, dried (Na₂SO₄),filtered and concentrated to an oil. Purification by sgc (EtOAc:hexanes)gave Compound 30 (1.4 g, 58%) as a gum.

[0226] Compound 31. Triethylsilane (3.5 mL, 22.5 mmol) was added to asolution of Compound 30 (0.6 g, 1.125 mmol) in CH₂Cl₂ (30 mL), followedby addition of boron trifluoride etherate (0.32 mL, 1.94 mmol). Afterstirring at rt for 15 min the reaction mixture was diluted with 50 mLCH₂Cl₂, washed with water, dried over Na₂SO₄, filtered, and concentratedto give a solid. Purification via PTLC (25%EtOAc/hexanes (1:3) gaveCompound 31 (0.47 g, 89%) as a solid.

[0227] Compound 32. MCPBA (1.56 g (56%), 5.09 mmol) was added to asolution of Compound 31 (0.47 g, 0.9 mmol) in CH₂Cl₂ (30 mL) at rt.After stirring for 16 h the reaction was washed with 5% aq NaHSO₃, aqNaHCO₃, and water. The organics were dried over Na₂SO₄, filtered, andconcentrated to give Compound 31 (0.4 g, 82%) as a solid.

[0228] Compound 33. 1 M aq LiOH (9.7 mL, 9.7 mmol) was added to asolution of Compound 32 (1.78 g, 3.2 mmol) in 1,4-dioxane (15 mL). Theresulting mixture was stirred overnight. The solvent was removed underreduced pressure and the residue was dissolved in 50 mL CH₂Cl₂ andwashed with 10 mL brine. The organics were dried over Na₂SO₄, filteredand concentrated to an oil, which was used in the next step withoutadditional purification.

[0229] Compound 34. Triethylamine (0.28 mL, 2 mmol) was added to asolution of Compound 33 (0.18 g, 0.4 mmol) in CH₂Cl₂ at rt, followed byaddition of MsCl (0.061 mL, 7.9 mmol ) in 0.2 mL CH₂Cl₂. The mixture wasstirred overnight, then washed with 2×10 mL water, dried over Na₂SO₄,filtered, and concentrated to give an oil. The oil was purified via PTLCusing EtOAc:hexanes (1:1) as the solvent to give Compound 34 (0.137 g,65%) as a solid.

[0230] Compound XIX. Triethylamine (0.296 mL, 2.1 mmol) was added to asolution of Compound 33 (0.4 g, 0.9 mmol) in 8 mL of CH₂Cl₂, cooled to0° C., followed by addition of a solution of trifluoromethanesulfonicanhydride (0.54 g, 1.9 mmol) in CH₂Cl₂ (5 mL). The mixture was stirredat 0° C. for 3 h, washed with water, dried over Na₂SO₄, filtered,concentrated under reduced pressure to give crude Compound XIX. Thecrude product was purified via PTLC using 33% EtOAc:hexanes to giveCompound XIX as a solid (0.32 g, 62%).

EXAMPLE XIV

[0231]

[0232] Compound XX. Triethylamine (0.018 mL, 0.129 mmol) was added to asolution of Compound 33 (0.05 g, 0.11 mmol) in CH₂Cl₂ (1.5 mL) followedby addition of 4-(trifluoromethoxy)benzenesulfonyl chloride (0.02 mL,0.118 mmol) in CH₂Cl₂ at rt. The stirring was continued for 10 h. Thereaction mixture was diluted with 50 mL CH₂Cl₂, washed with water, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by PTLC (33%EtOAc:hexanes to give Compound XX as asolid (0.048 g, 65%).

[0233] Compound XXI. Triethylamine (0.012 mL, 0.086 mmol) was added to asolution of Compound 33 (0.033 g, 0.073 mmol) in CH₂Cl₂ (1 mL) at −5° C.A solution of acetyl chloride (0.0057 mL, 0.08 mmol) in 0.5 mL CH₂Cl₂was added. The mixture was stirred overnight at rt. The organics werewashed with water, and then dried over Na₂SO₄, filtered, and thenconcentrated under reduced pressure. The resulting crude was purified byPTLC (EtOAc) to provide Compound XXI as a solid (0.009 g, 25%).

[0234] Compound XXII. Cyclopentyl isocyanate (0.0135 g, 0.12 mmol) wasadded as a CH₂Cl₂ solution (0.5 mL) to a solution of Compound 33 (0.05g, 0.11 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was stirred at rtovernight. The solvent was removed under reduced pressure and the crudeproduct was subjected to PTLC (EtOAc/hexanes 1:2) to provide CompoundXXII (0.04 g, 65%).

EXAMPLE XV

[0235]

[0236] Compound XXIII. N-Boc-piperazine (0.5 g, 2.68 mmol) was added toa solution of Compound XIX (0.2 g, 0.34 mmol) in CH₃CN (10 mL). Thereaction was heated at 80° C. for 72 h. Additional N-Boc-piperazine(0.25 g, 1.34 mmol) was added and heated at 80° C. for another 16 h. Thesolvent was removed under reduced pressure and the crude product waspurified via PTLC (50%EtOAc:hexanes) to provide Compound XXIII as asolid, (0.096 g, 37%).

EXAMPLE XVI

[0237]

[0238] Compound 35. Pyridinium chlorochromate (0.194 g, 0.899 mmol) wasadded to a mixture of Compound 30 (0.4 g, 0.75 mmol) and Celite (0.4 g)in CH₂Cl₂ (10 mL) at rt. The mixture was stirred for 18 h, filteredthrough Celite and concentrated. The crude material was purified viaPTLC using 33% EtOAc:hexanes to obtain Compound 35 (0.4 g, 100%).

[0239] Compound 36. MCPBA (1.29 g (56%), 4.18 mmol) was added to asolution of Compound 35 (0.4 g, 0.75 mmol) in CH₂Cl₂ (20 mL) and stirredat rt for 18 h. The reaction was washed with 5% aq NaHSO₃, 5% NaHCO₃,and water. The organics were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via PTLC usingEtOAc:hexanes (1:1) to provide Compound 36 (0.34 g, 80%).

[0240] Compound 37. Compound 36 was converted to Compound 37 using aprocedure similar to that described in example II.

[0241] Compound 38. LHMDS (0.9 mL, 1 M solution THF, 0.896 mmol) wasadded to a suspension of methyltriphenylphosphonium bromide (0.215 g,0.6 mmol) in anhydrous THF (10 mL) at 0° C. The mixture was stirred at0° C. for 20 min, then for 10 minutes at rt. A solution of Compound 36(0.17 g, 0.3 mmol) in THF (8 mL) was added and stirring continued for 10h at rt. The mixture was diluted with EtOAc and washed with water. Theorganics were dried over anhydrous Na₂SO₄, filtered and concentrated.The crude product was purified via PTLC using EtOAc:hexanes (1:3) toprovide Compound 38 as a solid. (0.09 g, 54%).

[0242] Compound XXIV. Compound 38 was converted to Compound XXIV using aprocedure similar to that described in example 11.

[0243] Compound XXV. Hydroxylamine hydrochloride (0.076 g, 1.09 mmol)was added to a solution of Compound 37 (0.03 g, 0.055 mmol) in pyridine(0.5 mL). The mixture was heated at 80° C. for 24 h. The mixture wascooled to rt and the solvent was removed under reduced pressure. Theresidue was dissolved in 50 mL CH₂Cl₂ and washed with water and brine.The organics were dried over Na₂SO₄, filtered and concentrated toprovide crude Compound XXV, which was purified via PTLC (EtOAc/hexanes,1:3) to afford Compound XXV as a solid (0.01 g, 33%).

EXAMPLE XVII

[0244]

[0245] Compound 39. In a flame dried flask under N₂ blanket, Compound 2(4.00 g, 10.32 mmol) was dissolved in anhyd THF (41 mL) and cooled to−78° C. A solution of n-BuLi (2.5 M in hexanes, 8.25 mL, 20.6 mmol) wasadded and the reaction mixture was stirred for 25 min.Bis-4-chlorophenyl disulfide (3.10 g/10.8 mmol) was added and thereaction mixture was stirred at −78° C. for 3 h then between −78° C. and−10° C. for 3 h. The reaction mixture was quenched with pH 7.0 sodiumphosphate buffer (1.0 M, 50 mL). The reaction mixture was partitionedbetween EtOAc and water. The organic layer was washed with brine, thendried with Na₂SO₄ and concentrated to dryness. The crude product (5.44 gfoam) was dissolved in CH₂Cl₂ (120 mL) and cooled to 0° C. MCPBA (7.24g) was added. The ice bath was removed and the reaction mixture wasstirred at rt overnight. Aqueous NaHCO₃ and CH₂Cl₂ were added and thelayers were separated. The organic layer was washed with aq NaHSO₃,NaHCO₃, H₂O, and brine then dried with MgSO₄. The crude product waspurified by sgc (35%-40% EtOAc/hexanes gradient) to give 1.86 g (32%) ofCompound 39.

[0246] Compound 40. Compound 39 (1.52 g, 2.70 mmol) was dissolved indioxane (9 mL) and cooled to 0° C. LiOH (1.0 M aq, 3 mL, 3 mmol) wasadded and the reaction mixture was left stirring overnight, during whichtime it warmed to rt. The solvents were evaporated. CH₂Cl₂ and aq NaOHwere added and the layers were separated. The aqueous layer wasextracted with additional CH₂Cl₂ and the combined organic layer wasdried with Na₂SO₄ and concentrated to give 0.85 g (68%) of Compound 40.

[0247] Compound XXVI. Compound 40 (143 mg, 0.307 mmol) was dissolved indioxane and sulfamide (0.128, 1.33 mmol) was added. The reaction mixturewas stirred at reflux for 24 h then allowed to cool to rt andconcentrated. The reaction mixture was purified via PTLC (5%MeOH/CH₂Cl₂) giving 54 mg (32%) of Compound XXVI.

EXAMPLE XVIII

[0248]

[0249] Compound 41. In a flame dried flask under N₂ blanket,1-chloro-4-fluorobenzene (7.36 g, 56.4 mmol) was dissolved in anhyd THFand cooled in a dry ice/acetone bath. n-BuLi (2.5 M in hexanes, 22.5 mL,56.3 mmol) was added and the reaction was stirred for 50 min.2-Fluorobenzene sulfonyl fluoride (10.3 g, 57.8 mmol) was added and thereaction mixture was left stirring overnight, during which time itwarmed to rt. Saturated aq NH₄Cl (100 mL) was added, followed by EtOAc(100 mL) and the layers were separated. The organic layer was washedwith water and brine, then dried with MgSO₄. The solvents wereevaporated and the crude product was purified via sgc (10%EtOAc/hexanes) to afford Compound 41 (2.55 g, 16%) as a solid.

[0250] Compound 42. 4-Mercaptobenzoic acid (0.54 g, 3.50 mmol) wasdissolved in DMA (10 mL) and cooled in an ice bath. Sodium hydride (60%suspension in oil, 0.30 g, 7.5 mmol) was added and the reaction mixturewas stirred for 20 min. The ice bath was removed and the reactionmixture was stirred for 1 h. The flask was cooled to 0° C. again andcompound 41 (1.0 g, 3.46 mmol) dissolved in DMA (5 mL) was added. Thereaction mixture was stirred at 0° C. for 30 min, then allowed to warmto rt and stirred overnight. The reaction mixture was diluted withCH₂Cl₂ and washed with 5% aq HCl, water, and brine. The organic layerwas dried with Na₂SO₄ and the solvents were evaporated. The crudeproduct was purified via sgc (5% MeOH/CH₂Cl₂) to give Compound 42 as asolid (1.04 g, 71%).

[0251] Compound 43. Pentafluorophenol (0.91 g, 4.94 mmol) and Compound42 (1.04 g, 2.46 mmol) were dissolved in 30 mL of CH₂Cl₂ and EDCl wasadded. The reaction was stirred overnight and diluted with water andCH₂Cl₂. The layers were separated and the organic layer was washed withwater and dried with Na₂SO₄. The crude product was purified via sgc (5%EtOAc/hexanes) to give 0.9 g (62%) of Compound 43 as a solid.

[0252] Compound XXVII. Compound 43 (0.15 g, 0.25 mmol) was dissolved inCH₂Cl₂ (5 mL). Morpholine (44 mg, 0.51 mmol) and DIPEA (49 mg, 0.38mmol) were added and the reaction mixture was stirred at rt for 2h. Thereaction mixture was diluted with EtOAc and washed with 5% aq NaHCO₃,water and brine. The organic layer was dried with Na₂SO₄ and thesolvents were evaporated. The crude product was purified via sgc (50%EtOAc/hexanes) to give 98 mg (77%) of Compound XXVII.

[0253] Compound XXVIII. Compound XXXVII (72 mg, 0.146 mmol) wasdissolved in CH₂Cl₂ (3 mL) and MCPBA (ca 50%, 0.11 g, ca 0.36 mmol) wasadded. The reaction mixture was stirred overnight then diluted withCH₂Cl₂. The reaction mixture was washed with aq Na₂CO₃ and water thendried with Na₂SO₄. The solvents were evaporated and the crude productwas purified via sgc (60% EtOAc/hexanes) to give 61 mg (79%) of CompoundXXXVIII as a solid.

EXAMPLE XIX

[0254]

[0255] Compound 44. Cyclopropyl benzene (48.5 g, 410 mmol), glacialacetic acid (510 mL), and sodium acetate (38.9 g, 474 mmol) were addedto a round bottomed flask. The flask was cooled in an ice-water bath. Asolution of bromine (66.3 g, 414 mmol) dissolved in 105 mL of aceticacid was added dropwise over 90 min. The reaction mixture was stirred attemperatures between 0° C. and 10° C. for 5 h. The reaction was thenallowed to warm to rt overnight. Hexanes (1300 mL) and water (250 mL)were added. Aqueous NaHSO₃ (1M) was added until the reaction mixturechanged from yellow to clear. The layers were separated. The organiclayer was washed with water, 1M aq Na₂CO₃, and brine, then dried withNa₂SO₄. The solvent was evaporated and the crude product was purifiedvia sgc using hexanes as the mobile phase to give 17 g ofp-cyclopropylbromobenzene (21%) (Compound 44).

[0256] Compound 45. A flask was flame dried under N₂ blanket. Compound44 (10.0 g, 50.7 mmol) was added, followed by dry THF (100 mL). Theresulting solution was cooled to −78° C. A solution of n-butyl lithiumin hexanes (2.27 M, 22.35 mL, 50.7 mmol) was added dropwise via syringe.The reaction mixture was stirred for 10 min. SO₂ gas was bubbled intothe reaction mixture until the pH of a reaction mixture sample was <1when mixed with water. The reaction mixture was stirred for 30 min at−78° C. The ice bath was removed and the reaction mixture was allowed towarm to rt. The reaction mixture was stirred for an additional 30 min atrt. The reaction mixture was concentrated to afford a solid. CH₂Cl₂ (500mL) and N-chlorosuccinamide (10.2 g, 76 mmol) were added and thereaction mixture was stirred for 4 hrs at rt. Water and CH₂Cl₂ wereadded and the layers were separated. The organic layer was washed withwater and brine, then dried with MgSO₄. The solution was filtered andthe solvents were evaporated to give 13.3 g of crudep-cyclopropyl-benzenesulfonyl chloride (Compound 45).

[0257] Compound 46. Crude compound 45 (13.3 g) was dissolved in 200 mLof acetone and 60 mL of water. Potassium fluoride (7.12 g, 122 mmol) wasadded and the reaction mixture was stirred overnight at rt. The reactionmixture was diluted with EtOAc and washed with water. The organic layerwas dried with Na₂SO₄, filtered, and concentrated to dryness to give9.80 g (97%) of crude p-cyclopropyl benzenesulfonyl fluoride (Compound46).

[0258] Compound 47. A flask was flame dried under N₂ blanket. Compound 1(44.29 g, 150 mmol) was added, followed by 500 mL of anhydrous THF. Theflask was cooled to −78° C. and a solution of n-butyl lithium in hexanes(1.77 M, 154 mL, 272 mmol) was added over 40 min. The reaction mixturewas stirred for 1.5 h at −78° C., then transferred via cannula into asolution of crude p-cyclopropylbenzenesulfonyl fluoride (27.2 g, 135mmol) dissolved in 200 mL of anhydrous THF over 1.5 h. The reactionmixture was stirred for 1 h. Water was added, followed by EtOAc. Thelayers were separated and the organic layer was washed with aq NH₄Cl,water, and brine, then dried with Na₂SO₄. The solvents were evaporated,and the crude product was purified by sgc (25%-33% EtOAc/Hexanesgradient mobile phase) to give 24.5 g (45%) of compound 47.

[0259] Compound 48. A flask was flame dried under N₂ blanket. Compound47 (16.33 g, 41.1 mmol) was dissolved in 400 mL of anhydrous THF andcooled to −78° C. A solution of n-butyl lithium in hexanes (2.3 M, 35.7mL, 82.1 mmol) was added dropwise via syringe. The reaction mixture wasstirred for 1.5 h at −78° C. A solution of 2, 2′-dithiodipyridine (8.89g, 41.1 mmol) dissolved in 40 mL of THF was added and the reactionmixture was stirred for 2 h. The cold bath was removed, and the reactionmixture was allowed to warm to rt overnight. The reaction mixture wascooled with an ice-water bath and the reaction was quenched with 10 mLof water. The reaction mixture was diluted with EtOAc and washed withsaturated aq NH₄Cl, water, and brine. The organic layer was dried withNa₂SO₄ and concentrated. The crude product was purified via sgc using1:2 EtOAc/Hexanes as the mobile phase giving 15.49 g (74%) of Compound48.

[0260] Compound 49. Compound 48 (15.49 g, 30.6 mmol) was dissolved in 1L of CH₂Cl₂ and the flask was placed in a rt water bath. MCPBA (22.0 g,ca 74 mmol) was added in portions and the reaction mixture was leftstirring overnight at rt. The reaction mixture was diluted with CH₂Cl₂and washed with 10% aq NaHCO₃, water, and brine, then dried with Na₂SO₄.The solvent was evaporated and the crude product was purified via sgcusing a 20%-50% EtOAc/Hexanes gradient as the mobile phase. Compound 49(9.4 g, 57%) was isolated as a solid.

[0261] Compound 50. Compound 49 (10.16 g, 18.87 mmol) was dissolved in300 mL of p-dioxane and 300 mL of 1.0 M aq LiOH was added. The reactionmixture was stirred at rt for 3 h. The reaction mixture was diluted withCH₂Cl₂. The layers were separated, and the organic layer was washed withwater and brine, then dried with Na₂SO₄. The solvents were evaporated togive 9.0 g of crude Compound 50.

[0262] Compound XXIX. Crude compound 50 (7.74 g, 17.5 mmol) wasdissolved in CH₂Cl₂ (250 mL). Diisopropylethylamine (2.71 g, 21 mmol)was added and the flask was cooled to −78° C. A solution of triflicanhydride (5.97 g, 21.1 mmol) dissolved in CH₂Cl₂ (50 mL) was addeddropwise over 1 h. The reaction mixture was stirred for 2 h at −78° C.The cold bath was removed, and the reaction mixture was allowed to warmto rt overnight. The reaction mixture was diluted with CH₂Cl₂ and washedwith water and brine. The organic layer was dried with Na₂SO₄ and thesolvents were evaporated. The crude product was purified via sgc using1:2 EtOAc/Hexanes as the mobile phase to give 8.61 g (85%) of CompoundXXIX.

[0263] Compound XXIX: ¹H NMR (300 MHz, CDCl₃): δ8.56-8.52 (m, 1H),8.32-8.21 (m, 3H), 8.02-7.92 (m, 4H), 5.42 (d, 9 Hz, 1H), 8.02-7.92 (m,4H), 5.42 (d, 1H, 9 Hz), 4.84-4.78 (m, 1H), 2.16-2.06 (m, 1H), 1.60 (d,7 Hz, 3H), 1.20-1.17 (m, 2H), 0.97-0.89 (m, 1H).

[0264] Compound XXX. Compound XXX was prepared from compound 47 usingthe procedures in example II.

[0265] Compound XXX: ¹H NMR (300 MHz, CDCl₃): δ8.33-8.22 (m, 3H),8.00-7.94 (m, 2H), 7.66-7.58 (m, 1H), 7.53-7.37 (m, 4H), 7.16-7.05 (m,1H), 5.160 (d, 9 Hz, 1H), 4.88-4.83 (m, 1H), 2.17-2.06 (m, 1H), 1.65 (d,7 Hz, 3H), 1.28-1.20 (m, 2H), 0.97-0.90 (m, 2H).

[0266] Compound XXXI. The potassium salt of compound XXIX (56 mg, 0.09mmol) was dissolved in CH₂Cl₂ (5 mL) and Na₂HPO₄ (0.13 g, 0.91 mmol),and urea-hydrogen peroxide complex (85 mg, 0.90 mmol) were added.Trifluoroacetic acid was added (47 mg, 0.22 mmol) and the reactionmixture was refluxed for 4 h then left stirring overnight at rt.Additional urea-hydrogen peroxide complex (85 mg, 0.9 mmol) and TFAA(0.56 mmol) were added and the reaction mixture was refluxed for 6 h.The reaction mixture was allowed to cool to rt and diluted with CH₂Cl₂and water. The layers were separated and the organic layer was washedwith water, dried with Na₂SO₄, and concentrated. The crude product waspurified via PTLC on silica using EtOAc as the mobile phase to give 34mg (64%) of compound XXXI.

[0267] Compound XXXI: ¹H NMR (300 MHz, CDCl₃): δ8.38-8.29 (m, 2H), 8.17(d, 8 Hz, 1H), 8.07-8.02 (m, 1H), 7.91-7.85 (m, 2H), 7.56-7.36 (m, 5H),6.11 (d, 8 Hz, 1H), 4.84-4.78 (m, 1H), 2.12-2.01 (m, 1H), 1.57 (d, 7 Hz,3H), 1.21-1.12 (m, 2H), 0.92-0.86 (m. 2H).

[0268] Compound XXXII. Compound V (0.50 g, 0.85 mmol), zinc (II) cyanide(65 mg, 0.55 mmol), zinc dust (11 mg, 0.17 mmol),1,1′-Bis(diphenylphosphino)ferrocene (21 mg, 0.04 mmol), andtris(dibenzylidineacetone) dipalladium (17 mg, 0.129 mmol) were added toa 25 mL flask. Dimethylacetamide was added and the reaction mixture wasplaced under N₂ blanket and heated to 110° C. The reaction mixture wasstirred at 110° C. for 4 h, then partitioned between EtOAc and water.The organic layer was washed with 2M ammonium hydroxide, water, andbrine, then dried with MgSO₄. Evaporation of the solvent afforded 0.49 gof an oil that was purified via sgc using a 20%-25% EtOAc/Hexanesgradient mobile phase to afford compound XXXII (0.20 g).

[0269] Compound XXXIII. Compound V (0.51 g, 0.87 mmol),tris(dibenzylidineacetone) dipalladium (40 mg, 0.04 mmol),2-(dicyclohexylphosphino)-biphenyl (36 mg, 0.103 mmol), and sodiumtert-butoxide (204 mg, 2.12 mmol) were added to a Schlenck flask underN₂ blanket. Toluene (2.5 mL) was added, followed by benzophenone imine(210 mg, 1.15 mmol). The reaction mixture was stirred overnight at 70°C. under N₂. The reaction mixture was allowed to cool to rt and 1 M aqHCl was added. The reaction mixture was diluted with EtOAc and thelayers were separated. The organic layer was washed with water andbrine, then dried with MgSO₄. The resulting material was filtered andconcentrated to give 0.37 g of an oil.

[0270] The crude product was purified via sgc using a 25%-50%EtOAc/Hexanes gradient mobile phase, followed by a5%MeOH/45%EtOAc/50%Hexanes mobile phase to give 0.11 g of an oil asproduct.

[0271] Compound XXXIV. Compound V (264 mg, 0.45 mmol), sodiumtert-butoxide (103 mg, 1.07 mmol), tris(dibenzylideneacetone)dipalladium (107 mg, 0.116 mmol), and2-(di-tert-butyl-phosphino)biphenyl (61 mg, 0.20 mmol) were added to aSchlenck flask under N₂. THF (1.5 mL) and cyclopropylamine (0.6 g, 10.5mmol) were added and the reaction mixture was stirred for 24 h at rt.EtOAc and 1 M aq HCl were added and the layers were separated. Theorganic layer was washed with 1 M aq HCl, water, and brine, then driedwith MgSO₄. Filtration and evaporation of the solvents gave an oil whichwas purified via sgc using 25% EtOAc/Hexanes as the mobile phase.Compound XXIV (109 mg) was obtained as a foam.

[0272] Compound XXXV. Compound XXXV was prepared from compound 5according to the procedures in Example XIX.

[0273] Compound XXXV: ¹H NMR (300 MHz, CDCl₃): δ8.88 (d, 1.2 Hz, 1H),8.51-8.56 (m, 2H), 8.31 (dd, 8 Hz, 1 Hz, 1H), 8.18 (dd, 8 Hz, 1 Hz, 1H),8.08-7.96 (m, 3H), 7.62-7.48 (m, 3H), 5.51 (d, 9 Hz, 1H), 4.90-4.70 (m,1H), 1.62 (d, 7 Hz, 3H).

[0274] Compound XXXVI. Compound XXXVI was prepared from compound XXXVaccording to the procedure in Example XIX.

[0275] Compound XXXVI: ¹H NMR (300 MHz, CDCl₃): δ10.19 (d, 7.8 Hz, 1H),8.27-8.42 (m, 4H), 8.13 (dd, 7.8 Hz, 2.1 Hz, 1H), 7.93 (d, 8.4 Hz, 2H),7.78-7.63 (m, 2H), 7.59 (d, 8.4 Hz, 2H), 4.80 (m, 1H), 1.44 (d, 6.9 Hz,3H).

[0276] Compound XXXVII. Compound XXXV (0.312 g, 0.548 mmol) wasdissolved in 2 propanol (20 mL) and 1.0 M aq NaOH was added (10 mL). Thereaction mixture was stirred at temperatures between 80° C. to 84° C.for six days. The reaction mixture was allowed to cool to rt andpartially concentrated. EtOAc was added and the layers were separated.The aqueous layer was acidified with 1 M aq H₂SO₄ and extracted withEtOAc. The combined organic layer was dried with MgSO₄ and concentratedto give 0.29 g of an oil. The crude product was purified via sgc using a25%-33% EtOAc/Hexanes gradient as the mobile phase. The fractioncontaining Compound XXVII was repurified via sgc using 3% MeOH/CH₂Cl₂ asthe mobile phase to give 0.05 g (15%) of Compound XXXVII as a solid.

[0277] Compound XXXVIII. Compound XXXVIII was prepared from compoundXXXV according to the procedure used to prepare compound XXXII.

[0278] Compound XXXIX. Compound XXXII (0.10 g, 0.17 mmol) was dissolvedin acetone (1.5 mL) and water (1 mL). Potassium carbonate (3 mg, 0.022mmol) and urea-hydrogen peroxide complex (0.16 g, 1.70 mmol) were addedand the reaction mixture was stirred overnight at rt. The reactionmixture was diluted with EtOAc and washed with water. The solvents wereevaporated and the crude product was purified via PTLC on SiO₂ using 50%EtOAc/Hexanes as the mobile phase to afford Compound XXXIX (75 mg, 73%)as a solid.

[0279] Compound XXXX. Compound XXXX was prepared from compound 2according to the procedures in Example II.

[0280] Compound XXXXI. Compound XXXXI was prepared from compound XXXXaccording to the procedure used to convert compound 16 to compound X.

[0281] Compound XXXXII. Compound XXXXI (0.15 g, 0.264 mmol) wasdissolved in DMA (5 mL). Potassium iodide (0.22 g, 1.30 mmol), cesiumcarbonate (0.19 g, 0.58 mmol), and 2-bromopropane (49 mg, 0.398 mmol)were added and the reaction mixture was left stirring at rt over theweekend. EtOAc was added and the reaction mixture was washed with satd.aq NH₄Cl and water. The organic layer was dried with Na₂SO₄ andconcentrated. The crude product was purified via sgc using 3%Et₂O/CH₂Cl₂ as the mobile phase to give 83 mg (51%) of Compound XXXXII.

[0282] Compound XXXXIII. Compound XXXXI (0.10 g, 0.176 mmol) wasdissolved in DMF (2 mL). Sodium hydride (7 mg, ca 1.2 eq) andbromomethylcyclopropane (26 mg, 0.19 mmol) were added and the reactionwas stirred at 50° C. for 4 hr then allowed to cool to rt. EtOAc andwater were added, and the layers were separated. The organic layer waswashed with water and dried with Na₂SO₄. The solvent was evaporated andthe crude product was purified via sgc using 33% EtOAc/Hexanes as themobile phase to give 15 mg (14%) of Compound XXXXIII.

[0283] Compound XXXXIV. Compound XXXXIV was prepared according to theprocedure used for Compound XXXXIII using ethyl iodide as theelectrophile and stirring the reaction at rt overnight before workup.

[0284] Compound XXXXV. Compound XXXXI (0.40 g, 0.70 mmol) was dissolvedin DMF (8 mL) and NaH (62 mg, ca 2.2 eq) was added. The reaction mixturewas stirred for 30 min. Sodium iodide (0.52 g, 3.46 mmol) and2-chloroethyl methyl ether (80 mg, 0.85 mmol) were added. The reactionmixture was stirred for 1 h at rt then 5 h at 110° C. The reactionmixture was allowed to cool to rt. EtOAc and satd aq NH₄Cl were addedand the layers were separated. The organic layer was washed with waterand dried with Na₂SO₄. Evaporation of the solvent, followed by sgc using50% EtOAc/Hexanes as the mobile phase, afforded 0.21 g (48%) of CompoundXXXXV.

[0285] Compound XXxXVI. Compound 50 (50 mg, 0.11 mmol) was dissolved inCH₂Cl₂ (3 mL) and acetic acid (7 mg). Acetone (6 mg, 0.13 mmol), andNaBH(OAc)₃ (36 mg, 0.169) were added, and the reaction mixture was leftstirring at rt overnight. EtOAc was added and the reaction mixture waswashed with 10% Na₂CO₃ and water. The solvents were evaporated and thecrude product was purified via PTLC on SiO₂ using EtOAc as the mobilephase. The resulting product was dissolved in EtOAc and HCl in Et₂O wasadded causing a white precipitate to form. The solvent was removed andthe precipitate was washed with Et₂O and dried in vacuo to give 32 mg(49%) of compound XXXXVI as a solid.

[0286] Compound XXXXVII. Compound XXXXVII was prepared according to theprocedure used for compound XXXXVI using cyclopentanone as the carbonylsource.

[0287] Compound XXXXVIII. Compound XXXXVIII was prepared according tothe procedure used for compound XXXXVI using cyclohexanone as thecarbonyl source

[0288] Compound XXXXIX. Compound XXXXIX was prepared according to theprocedure used for compound XXXXVI using cyclopropanecarboxaldehyde asthe carbonyl source.

[0289] Compound XXXXX. Compound XXVIII (0.10 g, 0.197 mmol) wasdissolved in a solution of borane in THF (1.0 M, 1.0 mL, 1.0 mmol). Thereaction mixture was refluxed for 4 h then allowed to cool to rt. Thesolution was concentrated. Methanol (5 mL) and 1 M aq HCl (5 mL) wereadded and the resulting solution was stirred for 5 h at rt. The reactionmixture was concentrated and EtOAc was added. The resulting solution waswashed with aq NaOH and water, then dried with Na₂SO₄. The solvent wasevaporated and the crude product was purified via PTLC using 40%EtOAc/Hexanes as the mobile phase. The product isolated from this stepwas dissolved in EtOAC, and HCl in Et₂O was added causing a precipitateto form. The solvent was removed and the precipitate was washed withEt₂O and dried in vacuo to give 22 mg (21%) of Compound XXXXX as asolid.

[0290] Compound 51 was prepared from Compound 2 according to theprocedures in Example 11.

[0291] Compound XXXXXI. Compound XXXXXI was prepared from compound 51according to the procedure used to prepare compound XXXXVI.

[0292] Compound XXXXXII. Compound XXXXXII was prepared from compound 51according to the procedure used to prepare compound XXXXVI using3-methyl-2-thiophenecarboxaldehyde as the carbonyl source.

[0293] Compound XXXXXIII. Compound XXXXXIII was prepared from compound51 according to the procedure used to prepare compound XXXXVI usingbenzaldehyde as the carbonyl source.

[0294] Compound 52. Compound 52 was prepared from compound 2 using theprocedures in Example II with benzenesulfonyl fluoride as the initialelectrophile.

[0295] Compound XXXXXIV. Compound 52 (0.29 g, 0.67 mmol), cesiumcarbonate (0.44 g, 1.35 mmol), tris(dibenzylideneacetone) dipalladium(31 mg, 0.034 mmol), dppp (28 mg, 0.068 mmol), and 2-bromopyridine (0.16g, 1.01 mmol) were dissolved in 11 mL of toluene under N₂ blanket. Thereaction mixture was stirred at 80° C. overnight under N₂, then allowedto cool to rt. CH₂Cl₂ was added and the reaction mixture was washed with2M aq NaHCO₃, water, and brine. The organic layer was dried with Na₂SO₄and the solvent was evaporated. The crude product was purified via sgcusing EtOAc as the mobile phase. The resulting material was dissolved inEtOAc and a solution of HCl/Et₂O was added. The solvents were evaporatedto give 145 mg (42%) of Compound XXXXXIV as a solid.

[0296] Compound XXXXXV. Compound XXXV (0.92 g, 1.67 mmol), was dissolvedin methanol (40 mL) and 1.0 M aq NaOH was added (20 mL). The reactionmixture was stirred at 70° C. for 21 h. The reaction mixture wasconcentrated and extracted with EtOAc. The organic layer was washed with1 M aq HCl, water, and brine, then dried with MgSO₄. The solvent wasevaporated and the crude product was purified via sgc using 25%-33%EtOAc/Hexanes as the mobile phase. Compound XXXXXV (0.82 g, 90%) wasisolated as an oil.

[0297] Compound XXXXV: ¹H NMR (300 MHz, CDCl₃): δ8.56 (d, 3.9 Hz, 1H),8.31-8.22 (m, 2H), 8.124 (d, 2.7 Hz, 1H), 8.05-7.95 (m, 1H), 7.92 (d,8.4 Hz, 2H), .750-7.45 (m, 1H), 7.92 (d, 8.4 Hz, 2H), 7.27-7.23 (m, 2H),5.8 (d, NH, 1H), 4.85-4.75 (m, 1H), 3.99 (s, 3H), 1.58 (d, 7.2 Hz, 3H).

[0298] Compound XXXXXVI. Compound 50 was converted to compound XXXXXVIaccording to the procedure in Example II.

[0299] Compound XXXXXVI: ¹H NMR (300 MHz, CDCl₃): δ8.56-8.52 (m, 1H),8.31-8.23 (m, 3H), 8.02-7.90 (M, 4H), 4.87-4.78 (d, 7 Hz, 1H), 4.69 (m,1H), 2.66 (s, 3H), 2.16-2.06 (m, 1H), 1.51 (d, 7 Hz, 3H), 1.27-1.17 (m,2H), 0.96-0.90 (m, 2H).

[0300] Compound 53. 2-fluoro-4-chloroaniline (22.90 g, 151 mmol) wasdissolved in 120 mL of AcOH and 80 mL of concentrated HCl was added withstirring. The reaction mixture was cooled to 0° C. and a solution ofNaNO₂ (27.2 g, 0.4 mol) dissolved in 40 mL of H₂O was added over 10 min.The reaction mixture was stirred for 30 min at 0° C. In a separateflask, 500 mg of CuCl was dissolved in 200 mL of AcOH. The flask wascooled to 0° C. and SO₂ gas was bubbled into the solution for 40minutes. The contents of the “aniline” flask were added to the contentsof the second flask over 20 minutes causing a vigorous evolution of gas.After the addition was complete, the ice bath was removed, and thereaction mixture was allowed to warm to rt. The reaction mixture waspoured into 500 g of chipped ice and the resulting solids werecollected, washed and dried to give 26.1 g (73%) of compound 53.

[0301] Compound 54. Compound 53 (4.0 g, 17.5 mmol) was dissolved inacetone (80 mL) and a solution of potassium fluoride (2.03 g, 35 mmol)in water (40 mL) was added. The reaction mixture was stirred at rtovernight. It was partially concentrated on the rotovap, thenpartitioned between CH₂Cl₂ and water. Evaporation of the solventafforded Compound 54 (2.60 g, 70%) as an oil.

[0302] Compound 55. Compound 55 was prepared from α-methyl benzylamineusing a procedure similar to that used to prepare compound 1.N-lodosuccinamide was substituted for DBDMH and the product wasrecrystallized from isopropanol/water.

[0303] Compound 56. Compound 55 (4.33 g, 12.5 mmol) was dissolved in THF(50 mL) and TMEDA (5.6 mL, 37 mmol) was added. The flask was placedunder N₂ blanket and cooled to 0° C. A solution of isopropyl magnesiumchloride (2.0 M in THF, 15 mL, 30 mmol) was added via syringe over 6min. The reaction mixture was stirred at 0° C. for 1 h. The resultingsolution was transferred via cannula into a flask containing compound 53(15 mmol) in an ice-water bath over 15 min. The reaction mixture wasleft stirring at 0° C. for 1.5 h. Aq NH₄Cl was added and the reactionmixture was extracted with EtOAc. The combined organic layer was washedwith brine and dried with MgSO₄. The solvents were evaporated and thecrude product was purified via sgc using 1:4 EtOAc/Hexanes as the mobilephase. Solid compound 56 (3.5 g, 68%) was obtained.

[0304] Compound 57. Compound 56 was converted to compound 57 usinghydrolysis and sulfonylation procedures similar to those described inExample II.

[0305] Compound 58. Compound 57 (0.10 g, 0.22 mmol) was dissolved in 1mL of dioxane and 2-mercaptoimidazole was added (28 mg, 0.28 mmol).Sodium hydride (60% dispersion in mineral oil, 18 mg) was added and thereaction mixture was stirred at 100° C. for 8 h. The reaction mixturewas quenched with ice and extracted with EtOAc. The organic layer wasdried with MgSO₄ and the solvents were evaporated. The crude product waspurified via sgc using a 5:95 MeOH/CH₂Cl₂ mobile phase to give 18 mg(15%) of compound 58 as product.

[0306] Compound XXXXXVII. Compound 57 was oxidized to compound XXXXXVIIusing a procedure similar to that used to oxidize Compound XIX tocompound XXI.

[0307] It will be understood that various modifications may be made tothe embodiments and examples disclosed herein. Therefore, the abovedescription should not be construed as limiting, but merely asexemplifications of preferred embodiments. Those skilled in the art willenvision various modifications within the pe and spirit of the claimsappended hereto.

We claim:
 1. A compound of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein: R¹ is H,alkyl, haloC₁-C₆ alkyl, cycloalkyl, cycloalkylNH—, arylalkyl,heterocycloalkyl, heteroaryl, N(R²)₂, or NR²aryl, unsubstituted aryl oraryl substituted with one to three X; R² is the same or different ineach occurrence and is independently selected from H or C₁-C₆ alkyl; R³is H, C₁-C₆ alkyl, Cl, F, CF₃, OCF₂H, OCF₃, OH or C₁-C₆alkoxy; R⁴ is H,C₁-C₆ alkyl, C₁-C₆alkoxy, cycloalkyl, alkenyl, aryl, benzyl, heteroaryl,heterocycloalkyl, arylNH—, heteroarylNH—, cycloalkylNH—, N(R²)₂, orNR²aryl, said alkyl, alkoxy, cycloalkyl, alkenyl, phenyl or heteroaryloptionally substituted with one to three X; R⁵ is H or C₁-C₆ alkyl; R⁶is H or C₁-C₆ alkyl; or R⁵ and R⁶ taken together with the carbon atomform a carbonyl group; L¹ is C₁-C₆ alkylene, C₂-C₆alkenylene, C(R²)₂,

 —CHOR²—, NOR⁵—, —SO₂—, —SO—, —S—, —O—, —NR²—, —C(O)NR²—, —NR²C(O)—,—CHCF₃— or —CF₂—; L² is a covalent bond, C₁-C₆ alkylene, —C (R²)₂—,

 —CHOR²—, —C(R²)OH, NOR⁵—, —SO₂—, —NR²SO₂—, —SO—, —S—, —O—, —SO₂NR²—,—N(R²)—, —C(O)NR^(2—) or —NR²C(O)—; X is the same or different, and isindependently selected from H, halogen, CF₃, CN, OCF₂H, OCF₂CF₃, OCF₃,OR², C₁-C₆ alkyl, cycloalkyl, cycloalkoxy, C₁-C₆ alkoxy, alkoxyC₁-C₆alkoxy, O-cycloalkyl, cycloalkylamino, cycloalkylalkoxy, heteroalkyl,—OSO₂R², —COOR², —CON(R²)₂, NHR², arylNH-, N(R²)₂, or NR² aryl; Y is acovalent bond, —CH₂—, —SO₂—, or

Z is a covalent bond, —CH₂—, —SO₂— or

Y, R¹, Z and R² can be taken together with the nitrogen atom to form aheterocycloalkyl; with the proviso that if Y is a covalent bond, R¹cannot form a N—N bond with the nitrogen atom; and n is an integer of 0to
 4. 2. A compound according to claim 1 wherein p1 L¹ is —SO₂—, —CH₂—,—CHCH₃—,

 —C═NOR²—, —C(CH₃)₂—, —CHOH—, —O—, —S— or —S═O; L² is —SO₂—,

 —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,

 —NH—, —O—, —NHSO₂—, —NHC(O)— or

R¹ is H, —CH₃NH₂, —CH₂CF₃, —NHC₃H₇, —NHC₂H₆, —NHC₄H₉, C₁-C₆ alkyl —CF₃,—CH(CH₃)₂, thiophenyl, morpholinyl, cyclopropanyl, benzyl, naphthyl,C(CH₃)₃, NHphenyl, 3,5-difluorophenyl, phenyl, N-cyclopentyl or N(CH₃)₂;R²is H or CH₃; R⁴ is furanyl, pyridyl, pyrimidyl, thiophenyl, quinolyl,t-butoxy, alkoxyl, cyclohexyl, phenyl, tolyl, C₃H₇, dimethylpyrimdyl,trifluoromethoxyphenyl, morpholinylphenyl or CH₃; with the proviso thatwhen R⁴is t-butoxy, L²must be

 —CH₂—, —CHCH₃—, —C(CH₃)₂— or

 all of the above optionally substituted with one to three substituents,which are the same or different and are independently selected from X;R⁵ and R⁶ are independently H or CH₃: X is H, Cl, CF₃, OCH₃, OCF₃,OCF₂H, CH₃ or C₁-C₆ cycloalkyl; Y is —SO₂— or

Z is a covalent bond; or R¹, Y, R² and Z taken together with thenitrogen atom form a morpholinyl group.
 3. The compound according toclaim 2 wherein L¹ is —SO₂— or —CH₂—; L is —SO₂—; R¹ is CH₃or CF_(3;)and R⁴ is phenyl, pyrimidyl or pyridyl, each of said phenyl, pyrimidylor pyridyl optionally substituted with one to three substitutents whichare the same or different, and are independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CF₃ and halogen.
 4. Thecompound according to claim 3 wherein the phenyl in R⁴ is substitutedwith OCH₃ or halogen.
 5. The compound according to claim 4 wherein thehalogen is selected from fluorine and chlorine.
 6. The compoundaccording to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X and R⁴ are asshown in the table below: X R⁴ OCH₃

OCH₃

OCF₂H

OCH₃

CH₃

OCH₃

OCF₃

Cl

Cl

OCH₃

CH₃

Cl

OCH₃

OCH₃

OCH₃ C₃H₇ CF₃

CF₃

CF₃

CF₃

Cl

Cl

Cl

Cl

Cl

Cl

Cl C₃H₇ OCF₃

OCF₃

OCF₃

OCH₃

OCH₃

CH₃

Cl

Cl

OH

OH

OCF₂H

H

H

H

H

H


7. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X and R⁴ are asshown in the table below: X R⁴ CF₃

Cl

Cl

CF₃

CF₃

CF₃

Cl

Cl

Cl

Cl

OCF₃

OCH₃

CH₃

CH₃

H

H

Cl

CF₃

Cl

OCH₃

OH

OCH(CH₃)₂


8. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X, R¹ and R⁴are as shown in the table below: X R¹ R⁴ OCH₃ CH₃

OCF₂H CH₃

CH₃ CH₃

Cl CH₃

CF₃ CF₃

Cl CF₃

CF₃ CH₃

Cl N(CH₃)₂

OCF₃ CH₃

OCF₃ CF₃

CH₃ CF₃

Cl CH₃

H CH₃

H CF₃

Cl CF₃

CF₃ CF₃

CF₃

CF₃

CF₃

CN CF₃

NH₂ CF₃

CF₃

Cl CF₃

Cl CF₃

CF₃

CN CF₃

—CONH₂ CF₃

—OCH₃ CF₃

—OH CF₃

CF₃

CF₃

CF₃

CF₃

OCH₃ CF₃

CH₃


9. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is OCH₃ andR¹ is CH₃.
 10. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is OCF₂H andR¹ is CH₃.
 11. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is CH₃ and R¹is CH₃.
 12. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is Cl and R¹is CH₃.
 13. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is CF₃ and R¹is CF₃.
 14. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is Cl and R¹is CF₃.
 15. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is CF₃ and R¹is CH₃.
 16. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is Cl and R¹is N(CH₃)₂.
 17. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is OCF₃ andR¹ is CH₃.
 18. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is OCF₃ andR¹ is CF₃.
 19. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is CH₃ and R¹is CF₃.
 20. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X iscyclopropyl and R¹ is CF₃.
 21. The compound according to claim 1 of theformula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is H and R¹is CH₃.
 22. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is H and R¹is CF₃.
 23. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is Cl and R¹is CF₃.
 24. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is CF₃ and R¹is CF₃.
 25. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X iscyclopropyl and R¹ is CF₃.
 26. The compound according to claim 1 of theformula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X is Cl and R¹is CF₃.
 27. The compound according to claim 1 of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X iscyclopropyl and R¹ is CH₃.
 28. The compound according to claim 1 of theformula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X iscyclopropyl and R¹ is CF₃.
 29. The compound according to claim 1 of theformula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug; wherein X iscyclopropyl and R¹ is CH₃.
 30. A pharmaceutical composition comprisingan effective amount of a compound, a prodrug thereof, or apharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, according to claim 1 and a pharmaceuticallyacceptable carrier.
 31. A pharmaceutical composition comprising aneffective amount of a compound, a prodrug thereof, or a pharmaceuticallyacceptable salt, solvate or stereoisomer of the compound or of saidprodrug, according to claim 7 and a pharmaceutically acceptable carrier.32. A method of stimulating cannabinoid CB₂ receptors in a mammalcomprising administering to a mammal having CB₂ receptors an effectiveCB₂ receptor stimulating amount of a compound, a prodrug thereof, or apharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, according to claim
 1. 33. A method oftreating cancer, inflammatory diseases, immunomodulatory diseases, orrespiratory diseases comprising administering to a mammal in need ofsuch treatment an effective amount of a compound, a prodrug thereof, ora pharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, according to claim
 1. 34. A method oftreating cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupuserythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock,sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia,retinal disease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, atopicdermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn'sdisease, inflammatory bowel disease, reversible airway obstruction,adult respiratory distress syndrome, asthma, chronic obstructivepulmonary disease (COPD), bronchitis, colitis, coronary artery disease,melanoma, transplant rejection, graft versus host disease, Hashimoto'sthyroiditis, Graves disease, myasthenia gravis or Goodpasture's syndromecomprising administering to a mammal in need of such treatment aneffective amount of a compound, a prodrug thereof, or a pharmaceuticallyacceptable salt, solvate or stereoisomer of the compound or of saidprodrug, according to claim
 1. 35. The method of claim 32 wherein thecondition or disease treated is selected from rheumatoid arthritis,multiple sclerosis, seasonal allergic rhinitis and chronic obstructivepulmonary disease.
 36. A pharmaceutical composition made by combiningthe compound, a prodrug thereof, or a pharmaceutically acceptable salt,solvate or stereoisomer of the compound or of said prodrug, of claim 1and a pharmaceutically acceptable carrier therefor.
 37. A process formaking a pharmaceutical composition comprising combining a compound, aprodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug, of claim 1 and apharmaceutically acceptable carrier.
 38. A method of treating rheumatoidarthritis which comprises co-administration of a compound selected fromthe class consisting of a COX-2 inhibitor, a COX-1 inhibitor, animmunosuppressive, a steroid, an anti-TNF-α compound or other classes ofcompounds indicated for the treatment of rheumatoid arthritis and acompound, a prodrug thereof, or a pharmaceutically acceptable salt,solvate or stereoisomer of the compound or of said prodrug, as definedin claim
 1. 39. A method of treating rheumatoid arthritis whichcomprises co-administration of a compound selected from the classconsisting of a COX-2 inhibitor, a COX-1 inhibitor, animmunosuppressive, a steroid, an anti-TNF-α compound, a PDE IV inhibitoror other classes of compounds indicated for the treatment of rheumatoidarthritis and a compound, a prodrug thereof, or a pharmaceuticallyacceptable salt, solvate or stereoisomer of the compound or of saidprodrug, as defined in claim
 7. 40. The method of claim 38 wherein theCOX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene,the immunosuppressive is methotrexate, leflunimide, sulfasalazine orcyclosporin, the steroid is β-methasone and the anti-TNF-α compound isEnbrel or Remicade.
 41. The method of claim 39 wherein the COX-2inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, theimmunosuppressive is methotrexate, leflunimide, sulfasalazine orcyclosporin, the steroid is β-methasone and the anti-TNF-α compound isEnbrel or Remicade.
 42. A composition for treating rheumatoid arthritiswhich comprises a compound selected from the class consisting of a COX-2inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, ananti-TNF-α compound or other classes of compounds indicated for thetreatment of rheumatoid arthritis and a compound, a prodrug thereof, ora pharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, as defined in claim
 1. 43. A compositionfor treating rheumatoid arthritis which comprises a compound selectedfrom the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, animmunosuppressive, a steroid, an anti-TNF-α compound or other classes ofcompounds indicated for the treatment of rheumatoid arthritis and acompound, a prodrug thereof, or a pharmaceutically acceptable salt,solvate or stereoisomer of the compound or of said prodrug, as definedin claim
 7. 44. The composition of claim 42 wherein the COX-2 inhibitoris Celebrex or Vioxx, the COX-1 inhibitor is Feldene, theimmunosuppressive is methotrexate, leflunimide, sulfasalazine orcyclosporin, the steroid is β-methasone and the anti-TNF-α compound isEnbrel or Remicade.
 45. The composition of claim 43 wherein the COX-2inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, theimmunosuppressive is methotrexate, leflunimide, sulfasalazine orcyclosporin, the steroid is β-methasone and the anti-TNF-α compound isEnbrel or Remicade.
 46. A method of treating multiple sclerosis whichcomprises co-administration of a compound selected from Avonex,Betaseron, Copaxone or other compounds indicated for the treatment ofmultiple sclerosis and a compound, a prodrug thereof, or apharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, as defined in claim
 1. 47. A method oftreating multiple sclerosis which comprises co-administration of acompound selected from Avonex, Betaseron, Copaxone or other compoundsindicated for the treatment of multiple sclerosis and a compound, aprodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug, as defined in claim 7.48. A composition for treating multiple sclerosis which comprises acompound selected from Avonex, Betaseron, Copaxone or other compoundsindicated for the treatment of multiple sclerosis and a compound, aprodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug, as defined in claim 1.49. A composition for treating multiple sclerosis which comprises acompound selected from Avonex, Betaseron, Copaxone or other compoundsindicated for the treatment of multiple sclerosis and a compound, aprodrug thereof, or a pharmaceutically acceptable salt, solvate orstereoisomer of the compound or of said prodrug, as defined in claim 7.50. A method of treating psoriasis which comprises co-administration ofa compound selected from the class consisting of an immunosuppressive, asteroid, an anti-TNF-α compound or other classes of compounds indicatedfor the treatment of psoriasis and a compound, a prodrug thereof, or apharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, as defined in claim
 1. 51. A method oftreating psoriasis which comprises co-administration of a compoundselected from the class consisting of an immunosuppressive, a steroid,an anti-TNF-α compound or other classes of compounds indicated for thetreatment of psoriasis and a compound, a prodrug thereof, or apharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, as defined in claim
 7. 52. The method ofclaim 50 wherein the immunosuppressive is methotrexate, leflunimide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.
 53. The method of claim 51wherein the immunosuppressive is methotrexate, leflunimide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.
 54. A composition fortreating psoriasis which comprises a compound selected from the classconsisting of an immunosuppressive, a steroid, an anti-TNF-α compound orother classes of compounds indicated for the treatment of psoriasis anda compound, a prodrug thereof, or a pharmaceutically acceptable salt,solvate or stereoisomer of the compound or of said prodrug, as definedin claim
 1. 55. A composition for treating psoriasis which comprises acompound selected from the class consisting of an immunosuppressive, asteroid, an anti-TNF-α compound or other classes of compounds indicatedfor the treatment of psoriasis and a compound, a prodrug thereof, or apharmaceutically acceptable salt, solvate or stereoisomer of thecompound or of said prodrug, as defined in claim
 7. 56. The compositionof claim 54 wherein the immunosuppressive is methotrexate, leflunimide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.
 57. The composition of claim55 wherein the immunosuppressive is methotrexate, leflunimide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.